determinants, correlates and modifiers of musculoskeletal · pdf fileethics and institutional...

Determinants, correlates and modifiers of

musculoskeletal pain

by

Laura Louise Laslett BSc(Hons) MMedSci GDPH

Menzies Research Institute Tasmania

Submitted in fulfilment of the requirements for the Degree of

Doctor of Philosophy (Medical Research)

University of Tasmania

June, 2013

Preamble

Preamble

Declaration of originality

This thesis contains no material which has been accepted for a degree or

diploma by the University or any other institution, except by way of

background information duly acknowledged in the thesis, and to the best of

my knowledge and belief no material previously published or written by any

other person except where due acknowledgement is made in the text of the

thesis, nor does the thesis contain any material that infringes copyright.

Signed: ………………………………………. Date: ……………………………

Preamble

Statement of Ethical Conduct

“The research associated with this thesis abides by the international and

Australian codes on human experimentation, and the rulings of the Safety,

Ethics and Institutional Biosafety Committees of the University.”

The Southern Tasmanian Health and Medical Human Research Ethics

Committee approved each study, and we obtained written informed consent

from all participants. Approval numbers are as follows:

Tasmanian Older Adult Cohort Study (TASOAC): H0006488

A randomised controlled trial of arthritis relief plus for osteoarthritis of the

knee (4Jointz study): H10988

Zoledronic acid in knee pain associated with bone marrow oedema (ZAP

trial): H0010319

Signed: ………………………………………. Date: ……………………………

Preamble

Statement of authority of access and regarding

published work

This thesis can be made available for loan. Copying of any part of this thesis

is prohibited for two years from the date this statement was signed; after that

time limited copying is permitted in accordance with the Copyright Act 1968.

The publishers of the papers comprising Chapters 5, 6, 7, and Appendix 2

hold the copyright for that content, and access to the material should be

sought from the respective journals. We as the authors hold copyright for the

paper comprising Chapter 4; this is an Open Access article.

Signed: ………………………………………. Date: ……………………………

Statement of authorship


This thesis includes papers for which Laura Laslett (LLL) was not the sole

author. LLL was the first author in the research of each manuscript;

however, she was assisted by the co–authors whose contributions are

detailed below.

Chapter 4

Laslett LL, Quinn SJ, Winzenberg TM, Sanderson K, Cicuttini F, Jones G. A

prospective study of the impact of musculoskeletal pain and radiographic

osteoarthritis on health related quality of life in community dwelling older

people. BMC Musculoskelet Disord. 2012 Sep 7;13(1):168.

LLL analysed the data, wrote the draft manuscript and completed revisions.

SJQ assisted with data analysis and provided statistical advice.

TW KS and FC contributed to discussions about the underlying patterns of

associations.

GJ designed the TASOAC study, the study from which the data in this

manuscript is taken, and formulated the hypotheses for this analysis.

All authors contributed to data interpretation, critically revised the manuscript

for important intellectual content, and read and approved the final

manuscript.

Chapter 5

Laslett LL, Quinn SJ, Burgess JR, Parameswaran V, Winzenberg TM, Jones

G, Ding C. Moderate vitamin D deficiency is associated with changes in knee

and hip pain in older adults: a five year longitudinal study. Ann Rheum Dis.

2013 [epub before print].

LLL analysed the data, wrote the draft manuscript and completed revisions.

SJQ provided statistical advice.

JB and VP contributed expertise and laboratory support for analysis of serum

samples for vitamin D metabolites.

TMW contributed epidemiological expertise.

GJ designed and obtained funding for the original TASOAC study and

contributed to the design of specific analyses.


CD formulated the hypotheses for this analysis and contributed to the design

of specific analyses.

All authors contributed to data interpretation, critically revised the manuscript

for important intellectual content, read and approved the final manuscript.

Chapter 6

Laslett LL, Quinn S, Darian-Smith E, Kwok M, Fedorova T, Körner H, Steels

E, March L, Jones G. Treatment with 4Jointz reduces knee pain over 12

weeks of treatment in patients with clinical knee osteoarthritis: a randomised

controlled trial. Osteoarthritis Cartilage. 2012;20(11):1209-16.

LLL dispensed medication, cleaned and analysed data, wrote the draft

manuscript and completed revisions.

SQ provided statistical advice.

ED-S and MK were involved in analysis of data.

TF was involved in acquisition of data.

HK provided technical expertise and advice on the laboratory tests.

LM was involved in the conception and design of the study.

GJ was involved in the conception and design of the study and obtained

funding.

LL, SQ, LM, ES and GJ were involved in data interpretation.

All authors were involved in drafting the article or revising it critically for

intellectual content, and all authors read and approved the final version to be

submitted.

Chapter 7

Laslett LL, Doré DA, Quinn SJ, Boon P, Ryan E, Winzenberg TM, Jones G.

Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a

randomised controlled trial. Ann Rheum Dis. 2012 Feb 21;71(8):1322-8.

LLL recruited patients, dispensed medication, cleaned and analysed data,

wrote the draft manuscript and completed revisions.

DAD read and interpreted MR images.


PB recruited and screened patients, and assisted with data collection.

ER assisted with data collection.

GJ designed the study, obtained funding and screened patients.


LLL, DAD, SJQ, TMW and GJ participated in data interpretation.

All authors critically reviewed and edited the manuscript and read and

approved the final version.

Appendix

Laslett LL, Just (nee Foley) SJ, Quinn SJ, Winzenberg TM, Jones G. Excess

body fat is associated with higher risk of vertebral deformities in older women

but not in men: a cross-sectional study. Osteoporos Int. 2012;23:67-74.

LLL extracted, cleaned and analysed the data, wrote the draft manuscript

and completed revisions.

SJJ read the morphometric DXA images.


TW provided the analysis idea of using a threshold.

GJ designed the TASOAC study, and formulated the hypotheses for this

analysis.

LLL, SJQ, TMW and GJ participated in data interpretation.

All authors critically reviewed and edited the manuscript, read and approved

the final version.

Signed by candidate, Laura Laslett

Signed: ………………………………………. Date: ……………………………

Signed by primary supervisor, Prof Graeme Jones:

Signed: ………………………………………. Date: ……………………………

Abstract

Abstract

Arthritis is the most common cause of chronic pain in older people. Pain is a

priority for patients and an important clinical symptom, as it predicts service

use, disability and joint replacements. Treatment options remain palliative,

and effect sizes suboptimal. This thesis investigates correlates, determinants

and modifiers of musculoskeletal pain.

The first study utilised data from TASOAC, a population of community

dwelling older adults aged 50–80 randomly selected from the electoral roll

and followed for five years to describe associations between aspects of

osteoarthritis (OA) and quality of life. This study identified that pain at all joint

sites is common in older adults, is stable over time, and is the strongest

musculoskeletal correlate of quality of life. Pain also mediates the association

between diagnosed OA and quality of life.

In the second study, in this same population, associations between serum

vitamin D (25–OHD) and change in knee and hip pain were investigated.

Moderate (but not mild) vitamin D deficiency independently predicted incident

or worsening in knee pain over 5 years and possibly hip pain over 2.4 years.

Therefore correcting moderate vitamin deficiency may attenuate worsening of

knee or hip pain in elderly persons but supplementing people with a higher

25–OHD level is unlikely to be effective.

In the third and fourth studies, potential modifiers of musculoskeletal pain

were investigated. In the former, efficacy of thrice daily topical 4Jointz

utilizing Acteev technology (a combination of a standardized comfrey extract

and pharmaceutical grade tannic acid, 3.5 g/day) vs placebo was assessed

on osteoarthritic outcomes over 12 weeks in participants aged ≥50 years with

Abstract

clinically defined knee OA, pain on most days, and VAS pain intensity

≥40mm (n=133). Topical treatment using 4Jointz reduced pain compared to

placebo (VAS -9.9 mm, p=0.034; KOOS pain scale +5.7, p = 0.047), but had

no effect on inflammation or cartilage breakdown over 12 weeks of treatment.

In the fourth study, efficacy of zoledronic acid (ZA: 5mg/100ml) vs placebo

over 12 months in participants aged ≥50 years with clinically defined knee

OA, pain on most days, VAS pain intensity ≥40mm and a bone marrow lesion

visible on T2-weighted MR images (n=59) was assessed. Treatment with ZA

(compared to placebo) improved VAS pain scores after six months (-14.5

mm, p=0.04) but not after three or twelve months. ZA treatment reduced

total BML area compared to placebo after six months (-175.7 mm2, p=0.024);

with a trend after twelve months (-146.5 mm2, p=0.095). This provided the

first evidence of a treatment to modify structural progression in OA.

In conclusion, this series of studies indicate that pain is a strong and stable

musculoskeletal correlate of quality of life over time, vitamin D is a

determinant of musculoskeletal pain, and treatment with 4Jointz and ZA are

both effective in reducing pain. Additionally, ZA modifies structural

progression by reducing total BML area; therefore, a lesion–specific

approach to treatment of osteoarthritis pain is feasible. Future work should

include targeting cognitive correlates of pain, clinical trials of vitamin D

supplementation, and clinical trials of ZA to investigate effects on cartilage.

Acknowledgements

Personal acknowledgements

I thank my primary supervisor, Professor Graeme Jones. When I first met him at a conference in 2003, he recommended that if I wanted to continue a career in science I should complete a PhD, and that he would be happy to supervise me. In late 2008 I contacted him to discuss taking him up on his offer… and so the PhD journey began. His advice has continued to be equally sound and timely, and I consider him an outstanding mentor. He has given generously of his time, advice, wisdom, opportunities and financial assistance. His input into critical thinking, particularly the craft of writing papers has increased my skills as a researcher. I am extremely fortunate to have had him as my primary supervisor during my PhD and I thank him for the many contributions he has made. I also thank my co–supervisors, Associate Professor Tania Winzenberg and Dr Steve Quinn. Tania has always been a hands–on and proactive supervisor. A year into my candidature she took me out to coffee and said “It’s great to have a solid relationship with a primary supervisor, but I want to know if there’s anything that you need from me that I’m not providing”. This was so like Tania, and I thank her for her skills, her timely encouragement, her willingness to listen when I needed political advice, and particularly her attention to detail with drafts of manuscripts and fellowships, which have become much better for Tania’s suggestions. Dr Steve Quinn has been my statistical supervisor. Early on in my candidature, he was willing to sit with me while I ran new analyses to help me identify and solve problems, and I thank him for his patience and time in this early period. Steve is extremely talented as a theoretical and practical statistician, and I am indebted to him for new ways of thinking about the art of statistical analysis. I thank him for continuing to make time for me, especially when he moved from Hobart to Adelaide. In this thesis, I have used data from the TASOAC study, the 4Jointz trial, and the ZAP trial. I thank the 1099 participants in the TASOAC study, the 59 participants in the ZAP trial and the 133 participants of the 4Jointz trial, who participated in these studies and without whom there would be no data. Running TASOAC involved many volunteers and research staff over five years. I thank research nurses Catrina Boon and Pip Boon, Jenny Cochrane (data manager), as well as technicians and other experts, including Dr Velandai Srikanth and Dr Helen Cooley (assessment of radiographs), Robert Warren (assessment of MR images), and Dr Guangju Zhai (scoring of bone marrow lesions). I thank the contributors to the 4Jointz trial in both the Hobart and Sydney sites, including Prof Lyn March (site co–coordinator, rheumatologist), Tanya Fedorova (research assistant), and the Royal North Shore Pharmacy (randomisation and local management of dispensing) at the Sydney site; and Melanie Clark, Jayne Dempster, and Margaret Green (research nurses), Kathy Buttigieg (laboratory analysis of IL–6 and CTX–2), and Mr Tim Albion

Acknowledgements

(development of study database, and generation of random allocation sequences) at the Menzies Research Institute Tasmania in Hobart, for their contributions. I thank Pip Boon (research nurse) and Dr Dawn Aitken (scoring of bone marrow lesions), and Mr Tim Albion (development of study database, and generation of random allocation sequences) for their contributions to the ZAP trial. I thank Professor Philip Conaghan, who agreed to fit me into his busy schedule and supervise me for 3 months while I was in the UK, and providing me with a stipend while I was in Leeds and my Australian scholarship was on hold. I also thank Dr Sarah Kingsbury, and all of the staff and students at the Division of Rheumatic and Musculoskeletal Disease at Chapel Allerton Hospital in Leeds, who welcomed me into life in the UK and looked after me while I was there. I very much enjoyed working with Philip and Sarah, observing different ways of working, and value the new perspective they have given me on musculoskeletal health, as well as our continuing collaborations. I thank the staff and students of the Menzies Research Institute Tasmania (both past and present), especially Dr Dawn Aitken (nee Dóre), Oliver Stannus, Dr Dave Scott, Sonja Nikolic, Harbeer Ahedi, Anitra Wilson and Kathy Thomson, and my new Hobart family, particularly our church family from Bethesda Mt Nelson and Kingborough Life Church. I thank my parents, Ray and Caroline Smith for their love, continuing support of me and my academic endeavours, and for giving me their blessing in leaving Adelaide. I thank my grandparents Kath and Charles Ford for their continuing support, unconditional love and regular phone calls. I am extremely grateful for the support of my whole family over many years. I thank my husband, Adam Laslett, for his support, cooking, housework, friendship, prayers, humour, unconditional love and always telling me how proud he is of me. I particularly thank him for his willingness to allow me to uproot us from Adelaide, in February 2009. We left behind our home town and our network of social and family support to come to Hobart where we had no family, no friends, no job for Adam, and where my salary would reduce by half. I am also extremely grateful that both of us took the risk in coming to Hobart, in obedience to what we felt was God’s best for us. We have had glimpses of the road not taken, and it is not pretty. But God is faithful, and life is good; the adventure of my PhD has largely been satisfying, and the last four years have been a happy and productive time in my life. Laura Laslett June 2013

List of publications

Financial acknowledgements

During my candidature I have had financial support from a number of sources including the Commonwealth of Australia (Australian Postgraduate Award) and an APA top–up scholarship, paid for by my supervisor Prof Graeme Jones. I also acknowledge the Osteoarthritis Research Society International (OARSI), who awarded me a Young Investigator Scholarship in March 2012, which enabled me to travel to Leeds (UK) for three months. I thank the numerous professional societies (listed in this thesis) who gave me bursaries to attend conferences. TASOAC TASOAC has received funding from many agencies, including: the National Health and Medical Research Council of Australia; Arthritis Foundation of Australia; Tasmanian Community Fund; Masonic Centenary Medical Research Foundation, Royal Hobart Hospital Research Foundation, and University of Tasmania Institutional Research Grants Scheme. 4Jointz trial I acknowledge Arthritis Relief Plus Ltd (Queensland, Australia), who provided tubes of 4Jointz and placebo, and finance for the study. ZAP trial I acknowledge Novartis Pharmaceuticals Australia for their funding of the ZAP trial and provision of zoledronic acid and placebo, and part–funding of the trial, and Prof Graeme Jones for his part–funding of the trial.



Publications arising from this thesis:

Laslett LL, Quinn SJ, Winzenberg TM, Sanderson K, Cicuttini F, Jones G. A

prospective study of the impact of musculoskeletal pain and radiographic

osteoarthritis on health related quality of life in community dwelling older

people. BMC Musculoskelet Disord. 2012;13(1):168.

Laslett LL, Dore DA, Quinn SJ, Winzenberg TM, Boon P, Jones G.

Zoledronic acid reduces knee pain and bone marrow lesions over one year: a

randomised controlled trial. Ann Rheum Dis 2012;71(8):1322-8.

Laslett LL, Quinn SJ, Darian-Smith E, Kwok M, Fedorova T, Körner H, Steels

E, March L, Jones G. Treatment with 4Jointz reduces knee pain over 12

weeks of treatment in patients with clinical knee osteoarthritis: a randomised

controlled trial. Osteoarthritis Cartilage. 2012, 20(11):1209-16.

Laslett LL, Quinn SJ, Burgess JR, Parameswaran V, Winzenberg TM, Jones

G, Ding C. Moderate vitamin D deficiency is associated with changes in knee

and hip pain in older adults: a five year longitudinal study. Accepted for

publication in Ann Rheum Dis in January 2013.

Manuscripts published during candidature, but

external to thesis material:

Redmond CL, Bain GI, Laslett LL, McNeil JD. Hand syndromes associated

with diabetes: impairments and obesity predict disability. J Rheumatol.2009;

36:2766-71.

Wei S, Winzenberg T, Laslett LL, Venn A, Jones G. Oral contraceptive use

and bone. Curr Osteoporos Rep, 2011;9(1):6-11.

Laslett LL, Lynch J, Sullivan TR, McNeil JD. Osteoporosis education

improves osteoporosis knowledge and dietary calcium: comparison of a four

week and a one-session education course. Int J Rheum Dis.

2011;14(3):239-47.

Valdes AM, De Wilde G, Doherty SA, Lories RJ, Vaughn FL, Laslett LL,

Maciewicz RA, Soni A, Hart DJ, Zhang W, Muir KR, Dennison EM, Wheeler

M, Leaverton P, Cooper C, Spector TD , Cicuttini F, Chapman V, Jones G,

Arden NK, Doherty M. The Ile585Val TRPV1 variant is involved in risk of

painful knee osteoarthritis. Ann Rheum Dis. 2011;70(9):1556-61.


Wei S, Venn A, Ding C, Foley S, Laslett L, Jones G. The association

between oral contraceptive use, bone mineral density and fractures in

women aged 50-80 years. Contraception. 2011 Oct;84(4):357-62.

Laslett LL, Just (nee Foley) SJ, Quinn SJ, Winzenberg TM, Jones G. Excess

body fat is associated with higher risk of vertebral deformities in older women

but not in men: a cross-sectional study. Osteoporos Int. 2012;23(1): 67-74.

Redmond CL, Bain GI, Laslett LL, McNeil JD. Deteriorating tactile sensation

in patients with hand syndromes associated with diabetes: a two-year

observational study. J Diabetes Complications 2012;26(4):313-8.

Crisp A, Dixon T, Jones G, Cumming RG, Laslett LL, Bhatia K, Webster A,

Ebeling PR. Declining incidence of osteoporotic hip fracture in Australia.

Arch Osteoporos. 2012 DOI 10.1007/s11657-012-0095-y

Vos T, et al. Years lived with disability (YLDs) for 1160 sequelae of 289

diseases and injuries 1990-2010: a systematic analysis for the Global Burden

of Disease Study 2010. Lancet. 2012;380:2163-96.

Murray CJ, et al. Disability-adjusted life years (DALYs) for 291 diseases and

injuries in 21 regions, 1990-2010: a systematic analysis for the Global

Burden of Disease Study 2010. Lancet. 2012;380:2197-223.

Laslett LL, Kingsbury SR, Hensor EMA, Bowes MA, Conaghan PG. Effect of

bisphosphonate use in patients with symptomatic and radiographic knee

osteoarthritis: data from the Osteoarthritis Initiative. Ann Rheum Dis.

2013[epub before print].

Scientific presentations and awards

Scientific presentations arising from the thesis

International conferences

2010 American Society for Bone and Mineral Research (Ontario, Canada). Laslett LL, Just S, Quinn S, Winzenberg TM, Jones G. Measures of body fat are associated with prevalent vertebral deformities in older women (Poster presentation).

2011 European League Against Rheumatism (London, UK). Laslett LL, Dore DA, Quinn SJ, Winzenberg TM, Boon P, Jones G. Zoledronic acid reduces bone marrow lesions and knee pain over one year (Oral presentation). This abstract won the award for “Best abstract” in the osteoarthritis section (€1000). This very prestigious award placed our abstract in the top 12 out of 3000 abstracts and recognises the novelty of the research question and quality of our research.

2011 Osteoarthritis Research Society International Imaging conference (Salzburg, Austria). Laslett LL, Dore DA, Quinn SJ, Winzenberg TM, Boon P, Jones G: Zoledronic acid reduces bone marrow lesions and knee pain over one year (Oral presentation). I was awarded a Young Investigator Award (€700) for this abstract. I was one of the top 4 Young Investigators selected to give an oral presentation in this specialist conference. I was also awarded half my travel costs (AUD$1900) from the University of Tasmania’s Graduate Research Conference Support Fund in order to attend this conference.

2011 Australia and New Zealand Bone and Mineral Society and the International Osteoporosis Foundation Regionals (Gold Coast, Australia). Laslett LL, Quinn SJ, Winzenberg TM, Jones G, Ding C. Low vitamin D predicts change in knee and hip pain over five years (Oral presentation). Laslett LL, Dore DA, Quinn SJ, Winzenberg TM, Boon P, Jones G. Zoledronic acid reduces bone marrow lesions and knee pain over one year (Poster presentation). I received a travel bursary to attend this conference and present this work (AUD$350).

2011 American College of Rheumatology (Chicago, USA). Hall J, Laslett LL, Martel-Pelletier J, Pelletier J-P, Abram F, Ding C, Cicuttini F and Jones G. Change in knee cartilage volume and incident meniscal extrusion as predictors of change in joint space width of the tibiofemoral joint: 5 year longitudinal study (Oral presentation). (Note: J Hall and LL Laslett joint first authors) This is a prestigious honour as only 5% of submitted abstracts are awarded an oral presentation.

2012 European Congress on Osteoarthritis and Osteoporosis (Bordeaux, France)


Laslett LL, Quinn SJ, Darian-Smith E, Kwok M, Fedorova T, Körner H, Steels E, March L, Jones G. Treatment with 4jointz reduces knee pain over twelve weeks of treatment in patients with clinical knee osteoarthritis: a randomised controlled trial (Poster presentation).

National conferences

2010 Australian Rheumatology Association (Melbourne). Laslett LL, Winzenberg TM, Quinn S, Jones G. Musculoskeletal determinants of quality of life in a community dwelling cohort of older people (Poster presentation). This poster won the award for “Best Clinical Poster” (AUD$500).

2010 Australia and New Zealand Bone and Mineral Society (Adelaide). Laslett LL, Just (nee Foley) SJ, Quinn SJ, Winzenberg TM, Jones G. Excess body fat is associated with higher risk of vertebral deformities in older women but not in men: a cross-sectional study (Poster presentation).

2012 Australian Rheumatology Association (Canberra). Laslett LL, Quinn SJ, Darian–Smith E, Kwok M, Fedorova T, March L, Jones G. Treatment with 4jointz reduces knee pain over twelve weeks of treatment in patients with clinical knee osteoarthritis: a randomised controlled trial (Poster presentation).

2012 Population Health Congress (Adelaide, Australia). Laslett LL, Quinn SJ, Burgess JR, Parameswaran V, Winzenberg TM, Jones G, Ding C. Serum vitamin D and change in knee and hip pain in older adults over five years (Oral presentation). I received a travel bursary to attend this conference and present this work (AUD$450).

Local conferences

2010 Sharing Excellence in Research, Graduate Research Conference of the University of Tasmania (Hobart). Laslett LL, Quinn SJ, Winzenberg TM, Jones G. Musculoskeletal determinants of quality of life in a community dwelling cohort of older people (Oral presentation).

2011 Sharing Excellence in Research, Graduate Research Conference of the University of Tasmania (Hobart). Laslett LL, Dore DA, Quinn SJ, Winzenberg TM, Boon P, Jones G: Zoledronic acid reduces bone marrow lesions and knee pain over one year (Poster presentation). This abstract won the award for “Best poster and best poster defence” (AUD$1000), as it was the top ranked poster of all posters presented at the University of Tasmania’s yearly postgraduate research conference.

2012 Sharing Excellence in Research conference (UTas postgraduate conference, Hobart). Laslett LL, Quinn SJ, Burgess JR, Parameswaran V, Winzenberg TM, Jones G, Ding C. Moderate vitamin D deficiency is associated with


new or worsening knee and hip pain in older adults: a five year longitudinal study (Poster presentation).


Awards resulting from thesis material

2010 Poster Prize: Best Clinical Poster at the Australian Rheumatology Association conference (Melbourne) for the poster “Musculoskeletal determinants of quality of life in a community dwelling cohort of older people”.

2010 Travel grant to attend the Australia and New Zealand Bone and Mineral Society (ANZBMS) Annual Scientific Meeting in Adelaide to present the poster entitled “Excess body fat is associated with higher risk of vertebral deformities in older women but not in men: a cross-sectional study”.

2011 Abstract Prize: Best abstract, Osteoarthritis section, European League against Rheumatism (EULAR) conference, London. Abstract title “Zoledronic acid reduces bone marrow lesions and knee pain over one year.”

2011 Poster prize: Best poster and best poster defence at the Sharing Excellence in Research Conference (UTas Graduate Research), Hobart for the poster entitled “Zoledronic acid reduces bone marrow lesions and knee pain over one year”.

2011 Travel grant to attend the Australia and New Zealand Bone and Mineral Society (ANZBMS) and the International Osteoporosis Foundation Regionals (Gold Coast). Annual Scientific Meeting in the Gold Coast. I gave an oral presentation entitled “Low vitamin D predicts change in knee and hip pain over five years” and defended a poster entitled “Zoledronic acid reduces bone marrow lesions and knee pain over one year”.

2012 Bursary to attend the Population Health Congress in Adelaide, Australia. I gave an oral presentation entitled “Serum vitamin D and change in knee and hip pain in older adults over five years”.

Other items awarded during candidature

2012 Arthritis Australia Fellowship 2013 (AUD$50,000). This is a competitive award offered to a junior investigator to further work in osteoarthritis. Only one fellowship is awarded annually.

2012 OARSI Young Investigator Scholarship (US$6500), March 2012. This is a competitive and prestigious award from the Osteoarthritis Research Society International (OARSI) which enabled travel to the UK for a 3 month placement at the Division of Rheumatic and Musculoskeletal Disease and NIHR Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds. Only 5 were awarded internationally.

2012 Menzies Research Institute Tasmania Postgraduate Student Prize, for best postgraduate student, awarded on the basis of excellent research achievement over the preceding 12 months (AUD$2000).

Abbreviations

List of abbreviations and approximate meanings

25–OHD 25-hydroxyvitamin D: the activated form of the hormone Vitamin D

ACR American College of Rheumatology

AQoL Assessment of Quality of Life: a questionnaire for assessing the

quality of a person’s life

BMI Body mass index: Quetelet’s index, a measure of fatness

BMD Bone mineral density: a two dimensional measure of bone density

BML Bone marrow lesion: a hypointense region in the bone marrow, as

visualised by magnetic resonance imaging

COX–2 cyclooxygenase–2: an enzyme responsible for inflammation and

pain

CTX–2 C-terminal cross linking telopeptide of type II collagen: a marker of

cartilage tissue degradation

DXA Dual energy X-ray absorptiometry: the current gold standard for

measuring bone mineral density

eGFR estimated glomerular filtration rate: a measure of kidney function.

FFQ Food frequency questionnaire: a dietary questionnaire

fMRI functional magnetic resonance imaging: an MRI procedure that

measures brain activity by detecting associated changes in blood

flow

ICC Intraclass correlation coefficient: a measure of the consistency of

measurements made by multiple observers measuring the same

data

IL–6 Interleukin–6, a marker of inflammation

IRR Incident rate ratio: a measure of relative risk

JSN Joint space narrowing: narrowing of the space between tibia and

femur, as seen on standing radiographs, inferring loss of cartilage

JSW Joint space width: the space between tibia and femur, as seen on

standing radiographs

KOOS Knee Injury and Osteoarthritis Outcome Score: a questionnaire

measure of knee pain and function

Abbreviations

MR Magnetic resonance

MRI Magnetic resonance imaging: a family of imaging techniques

enabling detailed visualisation of internal structures

NSAID Non-steroidal anti-inflammatory drugs: nonselective inhibitors of

both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-

2) isoenzymes, thereby reducing pain and inflammation.

Examples include aspirin, ibuprofen, naproxen and

cyclooxygenase–2 inhibitors such as celecoxib

OA Osteoarthritis

OARSI Osteoarthritis Research Society International

OARSI–OMERACT responder criteria

Osteoarthritis Research Society International (OARSI) standing

committee for clinical trials response criteria initiative and the

outcome measures in rheumatology (OMERACT) committee,

which in conjunction with the rheumatology community has led to

the development of a uniform core set of outcome measures for

osteoarthritis

OMERACT Outcome measures in rheumatology committee

OR Odds ratio: a measure of effect size

P1 Baseline (Phase 1) of TASOAC, the Tasmanian older adult cohort

study

P2 The 2.6 year follow up (Phase 2) of the TASOAC study

P3 The 5 year follow up (Phase 3) of the TASOAC study

QALY Quality adjusted life year: a metric used in health economics to

adjust years of life for the quality of the person’s life.

QoL Quality of life

RCT Randomised controlled trial

ROA Radiographic osteoarthritis: aspects of osteoarthritis as seen on

radiographs

SD Standard deviation: a measure of variation within a data set

SE Standard error: a measure of variation within a data set

TASOAC The Tasmanian Older Adult Cohort Study

VAS Visual analog score: a tool for measuring pain intensity

Abbreviations

WOMAC Western Ontario and McMaster Universities Index of

Osteoarthritis: a measure of knee and hip functioning

Note: Abbreviations appearing only in summary tables of treatment

modalities are not shown here.

Table of contents

Table of contents

Declaration of originality ................................................................................. 3

Statement of Ethical Conduct ......................................................................... 4

Statement of authority of access and regarding published work ..................... 5

Statement of authorship .................................................................................. 6

Abstract .......................................................................................................... 9

Personal acknowledgements ........................................................................ 11

Financial acknowledgements ........................................................................ 13

List of publications ........................................................................................ 14

Scientific presentations arising from the thesis ............................................. 16

Awards resulting from thesis material ........................................................... 19

Other items awarded during candidature ...................................................... 19

List of abbreviations and approximate meanings .......................................... 20

Table of contents .......................................................................................... 23

List of tables.................................................................................................. 29

List of figures ................................................................................................ 31

Chapter 1. Introduction to the determinants, correlates and modifiers of

musculoskeletal pain .................................................................................... 35

1.1 The importance and prevalence of pain........................................... 35

1.2 Arthritis ............................................................................................ 36

1.2.1 Disease burden and economic impact ...................................... 36

1.2.2 General definitions of osteoarthritis ........................................... 37

1.3 The nexus of pain and osteoarthritis: Radiographic vs. clinical

definitions of osteoarthritis ........................................................................ 38

1.4 Pain ................................................................................................. 40

1.4.1 Correlates of pain ...................................................................... 40

1.4.2 Pathogenesis of pain ................................................................. 45

1.4.3 Other determinants of pain ........................................................ 47

1.5 Treatment options for modifying musculoskeletal pain .................... 49

1.5.1 Evidence for efficacy of pain treatments ................................... 49

1.5.2 Evidence for side effects of pain treatments ............................. 54

Table of contents

1.5.3 Emerging bone–active treatments for musculoskeletal pain ..... 56

1.6 Summary ......................................................................................... 62

Chapter 2. Research questions ............................................................... 67

2.1 Research questions ......................................................................... 67

Chapter 3. Methodology .......................................................................... 71

3.1 Prelude ............................................................................................ 71

3.2 TASOAC design and study population ............................................ 71

3.2.1 Ethics ........................................................................................ 72

3.2.2 Baseline (Phase 1) .................................................................... 72

3.2.3 2.6 year follow up (Phase 2) ...................................................... 75

3.2.4 Five year follow up (Phase 3) .................................................... 78

3.3 Measurement of pain ....................................................................... 80

3.4 Study populations ............................................................................ 82

3.5 Study measures ............................................................................... 82

3.5.1 Anthropometrics ........................................................................ 82

3.5.2 Questionnaire measures ........................................................... 83

3.5.3 Strength and physical activity measures ................................... 85

3.5.4 X–ray ......................................................................................... 87

3.6 Summary of outcome factors, study factors, and covariates ........... 90

3.7 Statistical analysis ........................................................................... 92

Chapter 4. A prospective study of the impact of musculoskeletal pain and

radiographic osteoarthritis on health related quality of life in community

dwelling older people .................................................................................... 95

4.1 Introduction ...................................................................................... 95

4.2 Patients and methods ...................................................................... 96

4.2.1 Participants ............................................................................... 96

4.2.2 Quality of life ............................................................................. 97

4.2.3 Physician diagnosed osteoarthritis, pain and rheumatoid arthritis

97

4.2.4 X–ray ......................................................................................... 98

4.2.5 Other factors ............................................................................. 98

4.2.6 Data analysis ............................................................................. 99

4.3 Results ........................................................................................... 101

4.3.1 Participants ............................................................................. 101

4.3.2 Characteristics of the study population at baseline ................. 101

Table of contents

4.3.3 Correlates of quality of life at baseline: cross–sectional analysis

105

4.3.4 Correlates of quality of life over time: Longitudinal analysis .... 107

4.4 Discussion ..................................................................................... 109

Chapter 5. Moderate vitamin D deficiency is associated with changes in

knee and hip pain in older adults: a five year longitudinal study ................. 115

5.1 Introduction .................................................................................... 115

5.2 Patients and Methods .................................................................... 116

5.2.1 Study design, setting and participants ..................................... 116

5.2.2 Exposure: serum Vitamin D .................................................... 117

5.2.3 Outcomes: Knee and hip pain ................................................ 117

5.2.4 Knee and hip radiographs ....................................................... 118

5.2.5 Knee bone marrow lesions and cartilage defects .................... 118

5.2.6 Other factors ........................................................................... 119

5.2.7 Statistical methods .................................................................. 120

5.3 Results ........................................................................................... 121

5.3.1 Participants ............................................................................. 121

5.3.2 Descriptive data ...................................................................... 121

5.3.3 Proportion of participants reporting new or worsening pain .... 124

5.3.4 Change in knee and hip pain .................................................. 125

5.3.5 Sensitivity analyses ................................................................. 129

5.4 Discussion ..................................................................................... 130

Chapter 6. Treatment with 4Jointz reduces knee pain over 12 weeks of

treatment in patients with clinical knee osteoarthritis: a randomised controlled

trial 137

6.1 Introduction .................................................................................... 137

6.2 Methods ......................................................................................... 139

6.2.1 Trial design ............................................................................. 139

6.2.2 Settings and locations ............................................................. 139

6.2.3 Inclusion and exclusion criteria ............................................... 139

6.2.4 Participants ............................................................................. 140

6.2.5 Interventions ........................................................................... 140

6.2.6 Outcomes ................................................................................ 141

6.2.7 Outcome measures ................................................................. 141

6.2.8 Sample size ............................................................................ 143

Table of contents

6.2.9 Randomisation and sequence generation ............................... 144

6.2.10 Statistical methods ............................................................... 144

6.3 Results ........................................................................................... 145

6.3.1 Participants ............................................................................. 145

6.3.2 Outcomes ................................................................................ 148

6.3.3 Post-hoc analyses ................................................................... 152

6.3.4 Adverse events ....................................................................... 154

6.4 Discussion ..................................................................................... 155

Chapter 7. Zoledronic acid reduces knee pain and bone marrow lesions

over one year: a randomised controlled trial ............................................... 161

7.1 Introduction .................................................................................... 161

7.2 Patients and methods .................................................................... 162

7.2.1 Trial design .............................................................................. 162

7.2.2 Setting and participants ........................................................... 162

7.2.3 Randomisation and Interventions ............................................ 164

7.2.4 Outcomes ................................................................................ 164

7.2.5 Statistical analysis ................................................................... 167

7.3 Results ........................................................................................... 168

7.3.1 Participants ............................................................................. 168

7.3.2 Pain and symptom scores ....................................................... 170

7.3.3 Bone marrow lesion scores ..................................................... 173

7.3.4 Adverse events ....................................................................... 176

7.4 Discussion ..................................................................................... 177

Chapter 8. Summary and future directions ............................................ 183

8.1 Introduction .................................................................................... 183

8.2 Future directions ............................................................................ 183

8.2.1 Musculoskeletal pain and quality of life ................................... 183

8.2.2 Serum 25–OHD and change in knee and hip pain over time .. 184

8.2.3 4Jointz trial .............................................................................. 185

8.2.4 ZAP trial .................................................................................. 186

8.2.5 Challenges in clinical trials in osteoarthritis ............................. 187

8.2.6 Conclusions ............................................................................. 190

Appendix 1 Questionnaires ..................................................................... 193

A1.1 The Western Ontario and McMaster Universities Osteoarthritis

Index (WOMAC), and questions on diagnosed OA and joint pain ........... 193

Table of contents

A1.2 Smoking questions ..................................................................... 196

A1.3 Assessment of quality of life (AQoL) .......................................... 199

A1.4 Knee Injury and Osteoarthritis Scale .......................................... 203

Appendix 2 Excess body fat is associated with higher risk of vertebral

deformities in older women but not men: a cross–sectional study .............. 209

A2.1 Introduction................................................................................. 209

A2.2 Methods and procedures ............................................................ 212

A2.2.1 Participants .......................................................................... 212

A2.2.2 Anthropometrics ................................................................... 212

A2.2.3 Dual X-ray absorptiometry (DXA) ........................................ 212

A2.2.4 Quantitative morphometry.................................................... 213

A2.2.5 Other measures ................................................................... 213

A2.2.6 Data analysis ....................................................................... 214

A2.3 Results ....................................................................................... 215

A2.3.1 Participants .......................................................................... 215

A2.3.2 Prevalent vertebral deformities ............................................ 217

A2.3.3 Number of vertebral deformities ........................................... 221

A2.4 Discussion .................................................................................. 223

A2.5 Conclusions ................................................................................ 227

Appendix 3 A 12 week randomised controlled trial of 4Jointz for

symptomatic knee osteoarthritis ................................................................. 231

A3.1 Introduction................................................................................. 242

A3.2 Methods ..................................................................................... 245

A3.2.1 Trial design .......................................................................... 245

A3.2.2 Settings and locations .......................................................... 245

A3.2.3 Participants .......................................................................... 245

A3.2.4 Interventions ........................................................................ 246

A3.2.5 Outcomes ............................................................................ 247

A3.2.6 Outcome measures ............................................................. 247

A3.2.7 Sample size ......................................................................... 249

A3.2.8 Randomisation and sequence generation ........................... 249

A3.2.9 Statistical methods ............................................................... 250

Results .................................................................................................... 251

A3.3.1 Study participants ................................................................ 251

A3.3.2 Outcomes ............................................................................ 254

Table of contents

A3.3.3 Individual outcomes ............................................................. 257

A3.3.4 Post-hoc analyses ................................................................ 266

A3.3.5 Adverse events .................................................................... 271

Discussion ............................................................................................... 273

Conclusions ............................................................................................. 275

Appendix 4 Published manuscripts ......................................................... 279

Reference List ......................................................................................... 311

List of tables

List of tables

Table 1.1. Radiographic criteria for assessment of osteoarthritis using the Kellgren and Lawrence (KL) grading system ................................................ 38

Table 1.2: Best evidence for treatment efficacy for pain outcomes, from various modalities of therapy for hip and knee OA available 31 January 2009 (from Zhang, 2010) ....................................................................................... 50

Table 1.3: Side effects associated with pharmacological therapies. Adapted from Zhang, 2010 ......................................................................................... 54

Table 1.4: Experimental studies of bisphosphonates in patients with osteoarthritis, sorted by site and year of publication ..................................... 60

Table 3.1: Baseline demographic characteristics of those participants who completed Phase 1 (n=1099) and those who did not (n=1431) .................... 75

Table 3.2: Baseline demographic characteristics of those participants who completed Phase 2 (n=875) and those who did not (n=224) ........................ 77

Table 3.3: Characteristics of study cohort at baseline in participants who did and did not complete Phase 3 ...................................................................... 79

Table 3.4: Summary of when measures were assessed in the TASOAC study ...................................................................................................................... 89

Table 3.5: Summary of outcome factors, study factors, and covariates used in this thesis .................................................................................................. 90

Table 3.6. Study populations used in this thesis ........................................... 91

Table 4.1: Characteristics of the study population at baseline, by quality of life† .............................................................................................................. 102

Table 4.2: Assessment of Quality of Life (AQoL)† subscales at baseline: mean scores and range .............................................................................. 103

Table 4.3: Osteoarthritis correlates of total AQoL score at baseline, using linear regression ......................................................................................... 104

Table 4.4: Longitudinal analysis of arthritis correlates of total AQoL score over five years of follow up, using multilevel mixed–effects modelling ........ 108

Table 5.1: Characteristics of study cohort at baseline in participants who did and did not complete Phase 3 .................................................................... 121

Table 5.2: Characteristics of study cohort at baseline ................................ 123

Table 5.3: Association between serum 25–OHD and change in knee pain over 5 years, as assessed by the WOMAC questionnaire .......................... 127

Table 5.4: Association between serum 25–OHD and change in hip pain over 2.4 years, as assessed by the WOMAC questionnaire ............................... 128

Table 6.1: Baseline characteristics of study patients ................................. 147

Table 6.2: Effect of treatment with 4Jointz: change in study outcomes between baseline and four, eight and twelve weeks of treatment, and change in outcomes after treatment cessation (between twelve and sixteen weeks) .................................................................................................................... 150

List of tables

Table 6.3: Change in pain scores between baseline and twelve weeks by sex, OARSI grade and BMI, by treatment group ......................................... 153

Table 6.4: Prevalence and number of adverse events, by treatment received .................................................................................................................... 154

Table 7.1: Characteristics of study participants at baseline, by treatment received ...................................................................................................... 170

Table 7.2: Change in pain and knee symptoms, between treatment groups (per protocol analysis)................................................................................. 172

Table 7.3: Change in bone marrow lesion size between treatment groups (per protocol analysis)................................................................................. 173

Table 7.4: Change in bone marrow lesion area corresponding to clinically important improvement (≥140mm2) ............................................................. 175

Table 7.5: Adverse events .......................................................................... 176

Table A2.1: Demographics of study participants with and without one or more vertebral deformity (<20% height loss), by sex ........................................... 216

Table A2.2: Proportion of participants with anterior wedging (≥20%) by vertebra ....................................................................................................... 217

Table A2.3: Association between presence or absence of at least one vertebral deformity (≥20%) and measures of body fat in the thoracic spine stratified by sex †......................................................................................... 220

Table A2.4: Association between number of vertebral deformities (≥20%) and measures of body fat .................................................................................. 222

Table A3.1: Baseline characteristics of study patients ............................... 253

Table A3.2: Effect of treatment with 4Jointz: study outcomes after four, eight and twelve weeks of treatment, using change models ................................ 255

Table A3.3: Offset effect- change in study outcomes when treatment ceases (between 12 and 16 weeks of observation) ................................................ 256

Table A3.4: Change in pain scores between baseline and twelve weeks, by gender and treatment group ....................................................................... 266

Table A3.5: Change in VAS score between baseline and twelve weeks, by OARSI grade and body mass index. ........................................................... 269

Table A3.6: Prevalence and number of adverse events, by treatment received ...................................................................................................... 272

List of figures

List of figures

Figure 3.1: Flow chart of TasOAC recruitment and participation to end of Phase 1 ........................................................................................................ 74

Figure 3.2: Flow chart describing participation in Phase 2 of TASOAC ........ 76

Figure 3.3: Flow chart describing participation in Phase 3 of TASOAC ........ 78

Figure 3.4. Demonstration of the leg strength test performed in the TASOAC study (from Scott, 2010). .............................................................................. 86

Figure 5.1a: Proportion of TASOAC participants reporting incident or worsening knee pain on the WOMAC total pain scale and subscales over 5 years of observation, by category of baseline serum 25–OHD (p values using

2 tests) ....................................................................................................... 125

Figure 5.2: Boxplot of change in total knee WOMAC pain score over 5 years and change in total hip WOMAC pain score over 2.4 years, by categories of 25–OHD (nmol/L) at baseline. Knee pain: p for trend 0.002, threshold model (above / below 25 nmol/L) p=0.009. Hip pain: p for trend 0.63, threshold model p=0.026. Note: Interquartile range of change in hip WOMAC pain score in participants with 25–OHD of ≥50 nmol/L is 0 to 0. ........................ 126

Figure 6.1: Study flow chart ........................................................................ 146

Figure 6.2: Pain intensity (using visual analogue score) over the study time frame, using unadjusted data and 95% CI of the point estimates. p values are for the effect of treatment using change in VAS scores from baseline, excepting 16 weeks where p is for the effect of treatment cessation .......... 152

Figure 7.1 Participant flow diagram ............................................................ 169

Figure 7.2: Pain scores (visual analog scores) over the study time frame, using unadjusted data and 95%CI of the point estimates ........................... 171

Figure 7.3: Total bone marrow lesion area (mm2) by treatment group over twelve months, and 95% CI of the point estimates ..................................... 174

Figure A2.1: Association between body mass index and prevalence of vertebral deformities, by sex. Number of participants in individual groups listed above each bar. ................................................................................. 219

Figure A2.2: Association between body mass index and number of vertebral deformities (≥20%) stratified by sex ............................................................ 222

Figure A3.1: Study flow chart ...................................................................... 252

Figure A3.2: Pain intensity (using the visual analog scores) over sixteen weeks of treatment, by treatment received ................................................. 257

Figure A3.3: Pain intensity (as measured using the KOOS questionnaire) over sixteen weeks of treatment, by treatment received ............................. 259

Figure A3.4: Symptom scale, as measured using the KOOS questionnaire, over sixteen weeks of treatment, by treatment received ............................. 259

List of figures

Figure A3.5: CTX-2, by treatment received ................................................. 260

Figure A3.6: IL6, by treatment received ...................................................... 261

Figure A3.7: Proportion of participants using paracetamol over sixteen weeks of treatment, by treatment received ................................................. 262

Figure A3.8: Daily dose of paracetamol (mg) over sixteen weeks, in participants using paracetamol at baseline, by treatment received ............. 263

Figure A3.9: Leg strength over sixteen weeks of treatment, by treatment received ...................................................................................................... 264

Figure A3.10: Response to treatment using a modified version of the OMERACT – OARSI response criteria, by treatment received ................... 265

Figure A3.11a and b: Effect of treatment on pain intensity in women and men, by treatment received ........................................................................ 267

Figure A3.12 a and b: Effect of treatment on KOOS pain score in women and men, by treatment received ........................................................................ 268

Figure A3.13a and b: Effect of treatment on pain intensity in persons by OARSI grade (0 and 1 vs 2), by treatment received ................................... 270

Chapter 1: Introduction to the determinants, correlates and modifiers of musculoskeletal pain

Chapter 1: Introduction to the determinants, correlates and modifiers of

musculoskeletal pain


Chapter 1. Introduction to the determinants,

correlates and modifiers of musculoskeletal pain

1.1 The importance and prevalence of pain

Pain, the “unpleasant sensation associated with actual or potential tissue

damage...” (Dirckx, 1997), is a familiar human experience. It is an important

clinical symptom, and a priority for patients (Heiberg and Kvien, 2002).

Musculoskeletal pain predicts numerous clinically relevant outcomes,

including service use (Dominick, 2004), disability (Croft, 2005) and joint

replacements (Gossec, 2005; Hawker, 2006; Conaghan, 2010; Jüni, 2003).

Two important characteristics of pain are its frequency and intensity. The

exact prevalence of pain in any particular group depends upon the definition

used (Pereira, 2011) and the time reference. Overall prevalence of

musculoskeletal pain in community–dwelling adults appears to be

approximately 45–66% (Picavet and Schouten, 2003; Thomas, 2004; Zhai,

2006), and the prevalence of pain at most sites increases with advancing

age (Picavet and Schouten, 2003; Urwin, 1998), and is higher in

women (Picavet and Schouten, 2003; Zhai, 2006; Keenan, 2006).

Knees are either the most common (Keenan, 2006; Thomas, 2004) or one of

the most common sites of joint pain in older people (Picavet and Schouten,

2003). Pain of the hip or knee are also the sites in which the greatest age-

related increases in prevalence occurred (Picavet and Schouten, 2003).

Joint pain typically affects multiple joints (Picavet and Schouten, 2003;

Keenan, 2006; Thomas, 2004; Dawson, 2004).


1.2 Arthritis

The most common cause of chronic pain in older people is arthritis (Peat,

2001; Britt, 2010), from the Greek arthron (joint) and –itis meaning

(inflammation)), thereby being a (painful) disease characterised by

inflammation of a joint or joints (Dirckx, 1997)

1.2.1 Disease burden and economic impact

Based on self–reports, estimates from the 2007–08 National Health Survey

found that more than 6.3 million Australians (31%) have arthritis or some

other musculoskeletal condition. The most common type of arthritis is

osteoarthritis (OA), affecting 1.6 million Australians (8% of the population),

followed by rheumatoid arthritis, which is estimated to affect 429,000

Australians (2%). (Australia’s Health 2010 (AIHW, 2010)). OA

predominantly affects the large joints.

Of the 561,300 respondents to the National Health Survey who listed arthritis

or a related disorder as their main health condition, 30% rated limitations in

their core activities as severe or profound (ABS, 2003), showing that arthritis

can be extremely disabling.Arthritis and musculoskeletal conditions

constituted the fourth largest component of direct health expenditure in

2004–05, at 7.5% of allocated health expenditure or AUD$4.0 billion (AIHW,

2009), after cardiovascular diseases ($5.9 billion), oral health ($5.3 billion)

and mental disorders ($4.1 billion). Osteoarthritis costs are dominated by

admitted patient services, mostly related to knee and hip joint

replacements (AIHW, 2009), whereas in persons with rheumatoid arthritis,

around half of the direct costs were for prescription pharmaceuticals. Actual

expenditure on arthritis and musculoskeletal conditions increased from the

2000–01 to 2004–05 estimates, increasing annually by around 5.2% (after

adjusting for inflation and excluding research expenditure). Increases in


expenditure are predicted to continue by an estimated 223% between 2002–

03 and 2032–33 (Goss, 2008). Ageing, increases in the volume of

treatment(s) per case, and growing population are cited as the factors driving

these cost increases. Therefore, arthritis is common, disabling and

expensive. The burden of musculoskeletal disorders on the community has

been recognised on both national and international levels, with the Australian

Government declaring arthritis and musculoskeletal conditions as a national

health priority area in 2002, and at an international level with 2000–2010

declared the Bone and Joint Decade.

1.2.2 General definitions of osteoarthritis

OA was once described as a degenerative, or “wear and tear” disease, but

this is now considered incorrect (Creamer and Hochberg, 1997; Loeser,

2012). Osteoarthritis is now defined as a “progressive disease of synovial

joints that represents failed repair of joint damage that results from stresses

that may be initiated by an abnormality in any of the synovial joint tissues….

this ultimately results in the breakdown of cartilage and bone, leading to

symptoms of pain, stiffness and functional disability” (Lane, 2011).

Therefore, osteoarthritis is a disease of the whole joint, and although its

signature pathologic features are articular cartilage loss and damage of

adjacent bone (Arden and Nevitt, 2006), it commonly involves many other

joint structures including subchondral bone, ligaments, menisci, periarticular

muscles, peripheral nerves, and synovium (Lane, 2011; Loeser, 2012). The

failure of these joint tissues results in a common outcome – pain and reduced

function (Creamer and Hochberg, 1997), but involve no common pathological

pathway (Lane, 2011). Therefore, there must be a range of determinants of


disease, with different entities as potential therapeutic targets, not all of which

will benefit the entire patient population with osteoarthritis.

1.3 The nexus of pain and osteoarthritis: Radiographic vs.

clinical definitions of osteoarthritis

Osteoarthritis has historically been defined in two ways: firstly, using features

visible on radiographs without reference to pain. Examples include the

classic grading system of Kellgren and Lawrence (Kellgren and Lawrence,

1957) (see Table 1.1), or the more recent OARSI grading system (Altman,

1995), for grading osteoarthritis according to individual features visible on

radiographs (from 0–3, where 0=absent and 3=severe), rather than the joint

as a whole. Some advantages of using these radiographic classifications are

that they are objective, can be standardised, and the technology is well–

established, but disadvantages include the lack of correlation to the most

important concern of patients (pain) (Heiberg and Kvien, 2002), the inability

to visualise non-calcified tissues, their two–dimensional nature, measurement

error and semi-quantitative assessment (Jones, 2004).

Table 1.1. Radiographic criteria for assessment of osteoarthritis using the Kellgren and Lawrence (KL) grading system

Definition grades Description

Grade 0: No osteoarthritis No features of osteoarthritis Grade 1: Doubtful Minute osteophyte, doubtful significance Grade 2: Mild Definite osteophytes, unimpaired joint space Grade 3: Moderate Moderate diminution of joint space Grade 4: Severe Joint space greatly impaired with sclerosis of

subchondral bone

From Arden and Nevitt, 2006; based on Kellgren and Lawrence, 1957.

Secondly, OA can be defined clinically, such as the American College of

Rheumatology (ACR) definition which does include pain, specifically “pain for

most days of the month”, in addition to other clinical features (Altman, 1986).

These definitions are most useful for epidemiological and clinical studies


rather than clinical practice, as the initial criteria were designed to

differentiate patients with OA from those with rheumatoid arthritis (McAlindon

and Dieppe, 1989).

The relative importance of pain versus radiographic or imaging findings in

osteoarthritis is the subject of some debate (Cibere, 2006; LaValley, 2001).

Radiologic features are poor predictors of clinical outcomes, certainly in knee

osteoarthritis (Bruyere, 2002). Radiographic markers of osteoarthritis are

only weakly associated with pain (Bedson and Croft, 2008; Hannan, 2000;

Michel, 1997; Dahaghin, 2005), with only 15–53% of persons with knee pain

having prevalent radiographic OA using a global assessment scale, such as

the Kellgren–Lawrence system (Cibere, 2006). Results of a systematic

review and literature search investigating putative discordance between

clinical and radiographic knee osteoarthritis (Bedson and Croft, 2008)

concluded that reported discordance exists due to the nature and extent of

radiographic views (for example, patellofemoral joint views are often omitted),

how symptoms are defined, and the nature of the study group (Bedson and

Croft, 2008). When authors have attempted to control for potential reasons

for discordance, observed discordance reduces (Duncan, 2007). However,

lack of concordance does not equate to lack of aetiologic association. This

apparent discordance may simply reflect that there are many other factors

that cause pain other than structures that appear on radiographs.

Newer imaging modalities such as MRI allow visualisation of other structures

which have been associated with pain (Felson, 2001; Speer, 1992; Koo,

1999; Zhang, 2011), and a study from our centre showed that radiographic

features of knee OA (osteophytes, knee JSN) were not associated with

prevalent knee pain after adjustment for other structural factors (Zhai, 2006).


Therefore, it is clear that that investigation into correlates, determinants and

modifiers of musculoskeletal pain must look beyond radiographs.

1.4 Pain

1.4.1 Correlates of pain

Numerous studies have investigated correlates of pain, including

demographic and social factors as well as associations between features of

OA visible on radiographs and MR imaging. Correlates at several sites are

discussed in detail as follows.

1.4.1.1 Knee

Non-psychological correlates of knee pain have been well reviewed in Jones

et al, 2011 (Jones, 2011). Obesity, weak muscles, and numerous structures

have been independently associated with pain. These structures include

bone marrow lesions, cartilage defects, meniscal tears (posterior horn),

osteophytes (but not independently of MRI changes), joint effusions, and

synovitis. Tibial bone size, subchondral bone mass, meniscal extrusion and

cartilage volume are not associated with pain, and associations between

anterior cruciate ligament tears and knee pain are controversial (Jones,

2011). In our cohort, both prevalent knee pain and more severe knee pain is

associated with: increasing body mass index (BMI), reduced knee extension

strength, bone marrow lesions (BMLs), full–thickness and non–full–thickness

chondral defects of the medial tibial compartment, and hip (but not knee) joint

space narrowing (JSN), but not osteophytes (Zhai, 2006).

1.4.1.2 Hip

Less attention has been directed to pain at other sites. With regards to pain

in the hip, only a few authors investigated multiple correlates of hip

pain (Hopman-Rock, 1996; Juhakoski, 2008; Summers, 1988; Thumboo,

2002; van Baar, 1998), with only one of these studies solely investigating


persons with hip pain (Juhakoski, 2008) rather than a mixed population of

people with knee and hip pain.

Associations have been observed between number of comorbidities, duration

of concomitant knee pain, and life satisfaction, but not BMI, radiologic score

of hip OA, leg extensor strength or depression (as measured by the Beck

Depression Inventory (Juhakoski, 2008). BMI was associated with WOMAC

function scores, but not WOMAC pain (Juhakoski, 2008).

Regarding radiographic features of hip OA, synovitis, and possibly labrum hip

BMLs have been associated with hip pain cross–sectionally, after adjustment

for age, sex and BMI (Roemer, 2011). In another cross–sectional study,

BML size was found to be related to the magnitude of hip pain (Taljanovic,

2008). Indeed, prevalence of BMLs and synovitis was 100% in a sample of

patients with severe hip pain and rapidly progressing radiologic features of

hip OA (Boutry, 2002).

1.4.1.3 Low back

Cross–sectional correlates of low back pain include previous back injury,

physical and mental stress at work (Heliovaara, 1991), social

deprivation (Croft and Rigby, 1994; Webb, 2003) and pain at other

sites (Heliovaara, 1991; Webb, 2003). Correlations between low back pain

and clinical findings on physical examination are poor (Michel, 1997). A

systematic review of cohort studies found that psychological factors (notably

distress, depressive mood, and somatization) are implicated in the transition

from acute to chronic low back pain (Pincus, 2002). Conflicting findings on

the association between obesity and smoking with low back pain are

discussed later (see section 1.4.1.5: “Correlates across sites” on page 43).


Presence of vertebral endplate signal changes visible on MR imaging (Modic

changes) (de Roos, 1987; Modic, 1988) have been consistently associated

with low back pain symptoms, with a systematic review reporting significant

associations between Modic changes and low back pain (OR’s from 2.0 to

19.9) (Jensen, 2008). Patients with persistent Type 1 Modic changes have

poor prognosis over a follow up period of 14 months (Jensen, 2012), but

unlike knee BMLs, there is no association between the change in size of type

1 Modic changes and change in low back pain intensity (OR 1.0) (Jensen,

2012).

1.4.1.4 Hand

Dahaghin and colleages (Dahaghin, 2005) investigated correlates of hand

pain, finding that pain in the neck and shoulder, OA of any joint, female sex,

and presence of rheumatoid arthritis or a thyroid disorder were all associated

with hand pain in a multivariate model; but that diabetes, obesity, previous

fracture of the wrist or hand, or having a manual occupation were not. The

evidence for an association between radiographic OA and hand function

impairment is inconsistent, ranging from no association to a moderate

association (Dahaghin, 2006). Assessment of features using ultrasound

imaging, which showed that while persons with painful joints are more likely

to demonstrate ultrasound–detected pathology, the extent or total amount of

pathology observed did not correlate with symptoms (Keen, 2008), but the

sample size was small. Using MR imaging, synovitis, BMLs, erosions and

attrition have been associated with joint tenderness (Haugen, 2012).

Therefore, if pathological features are associated with pain, it appears more

likely that it will be the features visible on ultrasound and MR imaging rather

than those visible only on radiographs which are associated with pain.


1.4.1.5 Correlates across sites

Consistent correlates of pain across sites include psychological factors, poor

muscle strength, some OA features visible on MR imaging (eg BMLs,

synovitis), and pain in other joints. Features visible only on radiographs (eg

joint space narrowing) are consistently shown to be poorly correlated with

pain. Psychological factors are discussed in more detail in section 1.4.3

(page 47). Overall, many studies only investigate a few factors in cross–

sectional studies, whereas longitudinal studies are required to assess

changes over time.

BMI has been consistently associated with knee pain (Zhai, 2006; Felson,

2000) and low back pain (Leboeuf-Yde, 2000), but the lack of association in

the only study of multiple correlates of hip pain (Juhakoski, 2008) suggests

that at least some correlates of pain may differ by site of pain, a theory

supported by other authors (Adamson, 2006; Janke, 2007). Adamson

(2006) (65) (65) (65) reported cross–sectional associations between

obesity and pain in the lower limbs but not in the upper limbs, after

adjustment for sex, cigarette smoking, alcohol consumption and socio–

economic class. A review of 65 studies investigating obesity and low back

pain found that while obesity was weakly associated with low back pain,

results were inconsistent (Leboeuf-Yde, 2000). However, these studies have

used weight, BMI and waist–hip ratio, which do not provide information about

specific components of body composition and therefore no clues as to

possible mechanisms of action. A recent cross–sectional study investigated

the effect of different aspects of excess weight which may explain these

discrepancies. In multivariate analysis, they found that BMI was associated

with low back pain, as was total fat mass and lower limb fat mass (and

possibly upper limb fat mass), independent of lean mass, but that lean mass


was not associated with pain independent of fat mass (Urquhart, 2011). This

suggests that the relationship between obesity and low back pain intensity

includes spinal loading as well as metabolic factors.

Adamson (2006) (65) (65) (65) also reported associations between

cigarette smoking and pain in the upper limbs after adjustment for sex,

alcohol consumption and socio–economic class. This reached statistical

significance for back and shoulder pain, but not at other sites (Adamson,

2006). There has been significant debate about the role of cigarette smoking

as a correlate or cause of pain and OA, particularly in the light of a recent

study (a longitudinal observational study following up a cohort who had taken

part in an earlier randomised controlled trial). This demonstrated a strong

inverse dose–response relationship between duration of smoking and risk of

lower limb total joint replacement (Mnatzaganian, 2011). This is in contrast

to data from other observational studies, which show that the protective effect

of smoking in OA is likely to be false and related to selection bias in the

control populations of case–control studies, as it was observed only in

hospital–based case–control studies (Hui, 2011; Gill and Hill, 2012). Indeed,

our data suggest smoking is detrimental for spinal OA (Jones, 1998), and

cartilage loss in the knee (Ding, 2008) in cross–sectional studies.


1.4.2 Pathogenesis of pain

The pathogenesis of pain is complex and multifactorial, involving local

nociception, inflammatory mediators, and central sensitisation.

Normal cartilage is aneural, but abnormal cartilage is not, with evidence of

substance P nociceptive fibres in osteoarthritic cartilage (Fortier and Nixon,

1997; Wojtys, 1990), suggesting that these fibres are involved in the

signalling and maintenance of pain associated with OA. Other work has

demonstrated that prostaglandins are differently regulated in normal and OA-

affected chondrocytes, with up–regulation of cyclooxygenase-2 (COX-2) in

cartilage specimens from persons with OA, leading to a 50 fold increase in

prostaglandin E2 (Amin, 1997), which then stimulates bone

resorption (Robinson, 1975). This all suggests that abnormal cartilage has a

direct role as a source of pain. There is increasing interest in the subchondral

bone in the pathogenesis of OA, and therefore it is interesting and relevant

that substance P nocioceptive fibres have also been found in the

subchondral bone (Wojtys, 1990).

Inflammatory processes are implicated in the pathogenesis of

musculoskeletal pain. Inflammation can be localised (eg synovitis) or

systemic, as indicated by changes in inflammatory markers such as IL–6.

Biopsies of patients with both early and late knee OA have shown low-grade

chronic synovitis with production of pro–inflammatory cytokines (Smith, 2003;

Benito, 2005). Synovitis has been associated with fluctuations in pain (Hill,

2007; Zhang, 2011), and interventions aimed at the synovium are effective in

treating knee pain, such as intra-articular injections of local

anaesthetic (Creamer, 1996), and corticosteroids


(Dieppe, 1980; Ostergaard, 1996; Raynauld, 2003). Since other evidence

suggests that the synovium is richly innervated (Kidd, 1996), overall, this data

suggests that there is an intra–articular component to knee pain, and that this

is likely to be due to inflammatory factors.

The consistent association between presence of BMLs and knee

pain (Felson, 2001; Felson, 2007; Zhang, 2011; Zhai, 2006), and Carbone’s

observations that BMLs were significantly less common in users of

alendronate and oestrogen (Carbone, 2004) suggest that bisphosphonates

and BMLs (and indeed the subchondral bone as a whole) may provide

insights in the pathogenesis of pain as well as potential treatments (see

Chapter 1.5.3 for further exploration of this second theme). BML–related

pain could be osteoclast–mediated, since this is one mechanism of action of

nitrogen-containing bisphosphonates (Rogers, 2003), and a known

mechanism of bone pain in cancer (Honore and Mantyh, 2000), which is

often treated with bisphosphonates.

Bisphosphonates may work through a variety of mechanisms, including

effects on the subchondral bone and osteochondral junction. Abnormal bone

turnover in OA leads to a zone of osteoporosis beneath the thickened

subchondral plate, altered flexibility, and increased microfracture (Buckland-

Wright, 2007). Osteoclasts mediate the extension of channels from marrow

spaces into the non-calcified articular cartilage. The resulting loss of

osteochondral integrity exposes subchondral nerves to pro–inflammatory and

algesic factors from the synovial fluid and permits sensory nerve growth into

the non–calcified articular cartilage (Walsh, 2010). Furthermore, osteoclasts

may reduce pH at the osteochondral junction, thereby sensitizing and

activating sensory nerves through actions on ion channels on their peripheral


terminals (Yoneda, 2011). Bisphosphonates are also reported to have anti-

inflammatory actions (Roelofs, 2010; Baroja-Mazo and Pelegrin, 2012); such

effects may play a role in an immediate analgesic benefit, as distinct from

that which might arise as a consequence of osteochondral structural

alteration. Overall, it is clear that the pathogenesis of joint pain is complex

and multifactorial, involving local nociception, inflammatory mediators, and

central sensitisation (Dieppe and Lohmander, 2005; Kidd, 1996; Schaible

and Grubb, 1993), but also that a lesion-specific approach is feasible in

treating joint pain.

1.4.3 Other determinants of pain

The pain experienced by an individual is strongly influenced by

genetics (Foulkes and Wood, 2008), including genes for thermal pain

sensitivity. For example, analyses completed by UK colleagues in

collaboration with our group used pooled data from 7 cohorts (including

TASOAC) demonstrated that persons having the TRPV1 585 Ile–Ile

genotype (associated with lowered peripheral pain sensitivity) were at

decreased risk of knee OA being painful (OR 0.74) (Valdes, 2011). This

further demonstrates that factors other than radiographic changes influence

pain.

Vitamin D has also been implicated in the pathogenesis of knee pain, as

vitamin D deficiency is common in persons with widespread bone and muscle

pain (McBeth, 2010; Plotnikoff and Quigley, 2003; Block, 2004; Al Faraj and

Al Mutairi, 2003; Nellen, 1996; Serhan, 1999), although this could be reverse

causality through the effects of ill health on sunlight exposure and physical

activity. The active metabolite 1,25(OH)2D has an antiproliferative effect and

down-regulates inflammatory markers (Lips, 2006). We have demonstrated


in a smaller sample of our cohort that inflammatory markers are associated

with change in non-weight bearing knee pain (Stannus, 2013). Other authors

have shown that low levels of 25–OHD predicted increased experimental

pain sensitivity (Glover, 2012), suggesting that vitamin D level may be related

to pain pathways involved in initial perception of pain.

Cognitive, psychological, and psychosocial aspects also influence

pain (Keefe and Somers, 2010; Creamer, 1999), with depressed persons

experiencing more rapid worsening in knee pain than non–depressed

persons (Riddle, 2011). Causality also occurs in the opposite direction;

osteoarthritic knee or hip pain were determinants of subsequent depressed

mood through its effect on fatigue and disability (Hawker, 2011).

Pain catastrophisation has been extensively investigated. It refers to the

tendency to focus on and magnify pain sensations, and to feel helpless in the

face of pain (Sullivan, 2001). It explains a higher proportion of variance in

pain cross–sectionally than demographic and medical status variables

combined (Somers, 2009) and mediates the gender–pain relationship even

after controlling for depression (Keefe, 2000). Catastrophisation is related to

pain severity, pain–related disability, poor outcomes of pain treatment, and

possibly inflammatory disease activity (Edwards, 2006).


1.5 Treatment options for modifying musculoskeletal pain

There are a number of treatment options for modifying musculoskeletal pain.

Guidelines for the use of these therapies for OA of the knee and hip have

been developed by the relevant professional society (OARSI) (Zhang, 2008).

Optimal management of the symptoms of hip and knee OA include a

combination of non–pharmacological and pharmacological

modalities (Zhang, 2008), with provision of information about the disease

process and lifestyle modification, physical activity, weight loss and

appropriate referral to health professionals eg physiotherapist. The initial oral

analgesic for pain relief is paracetamol (<4g/day) followed by non–steroidal

anti–inflammatory drugs, COX–2 selective agents or non–selective NSAIDs

co–prescribed with proton–pump inhibitors for prevention of gastro–intestinal

side effects. If pain persists, other available therapies include capsaicin,

injections of corticosteroids, glucosamine sulphate, chondroitin sulphate, and

weak opioids. Patients who continue to have inadequate pain relief and

functional improvement may consider joint replacement surgery (Zhang,

2008).

1.5.1 Evidence for efficacy of pain treatments

Evidence summaries have now been developed for treatment of

musculoskeletal pain, within the context of knee and hip OA (Zhang, 2010).

Table 1.2 has been reprinted from Osteoarthritis Cartilage, Vol 18, Zhang W

et al. OARSI recommendations for the management of hip and knee

osteoarthritis: part III: Changes in evidence following systematic cumulative

update of research published through January 2009, pg 476-99, Copyright

(2010), with permission from Elsevier. Effect sizes (ES) are standard mean

difference (i.e., the mean difference between a treatment and a control group


divided by the standard deviation of the difference), and are presented for

function and stiffness. References to original papers have been omitted.

Table 1.2: Best evidence for treatment efficacy for pain outcomes, from various modalities of therapy for hip and knee OA available 31 January 2009 (from Zhang, 2010)

Modality Joint QoS (%)

LoE Effect size for pain (95% CI)

NNT (95% CI)

Non-pharmacological

Self-management Both 100 Ia 0.06 (0.02, 0.10)

Telephone Both 100 Ia 0.12 (0.00, 0.24)

Education Both 100 Ia 0.06 (0.03, 0.10)

Strengthening Knee 100 Ia 0.32 (0.23, 0.42)

Hip 100 Ia 0.38 (0.08, 0.68)

Aerobic Knee 100 Ia 0.52 (0.34, 0.70)

Water-based exercise Both 100 Ia 0.19 (0.04, 0.35)

Balneotherapy Knee 75 Ia NS

Spa/sauna Both 75 Ib 0.46 (0.17, 0.75) NS

Weight reduction Knee 100 Ia 0.20 (0.00, 0.39) 3 (2, 9)

TENS Both 75 Ia 2 (1, 5)

Laser Both 100 Ia 4 (2,17)

Ultrasound Both 50 Ia 0.06 (-0.39, 0.52)

Radiotherapy Both 50 IIb Similar effects between OA and RA from an MA of uncontrolled trial

Heat/ice Knee 75 Ia 0.69 (-0.07, 1.45)

Massage Knee 40 Ib 0.10 (-0.23, 0.43)

Acupuncture Knee 100 Ia 0.35 (0.15, 0.55) 4 (3, 9)

Insoles Knee 100 Ia No different between type of insoles, no placebo/usual care comparisons

Joint protection (braces)

Knee 100 Ia More benefits with a knee brace than a neoprene sleeve

Electrotherapy/EMG Knee 100 Ia 0.16 (-0.08, 0.39)

(Table continues on the next page)


Table 1.2 Best evidence for treatment efficacy for pain outcomes (cont.)

Modality Joint QoS (%)

LoE Effect size for pain (95% CI)

NNT (95% CI)

Pharmacological

Acetaminophen Both 100 Ia 0.14 (0.05, 0.23) 3 (2, 52)

NSAIDs Both 100 Ia 0.29 (0.22, 0.35)

Cox-2 inhibitors Both 100 Ia 0.44 (0.33, 0.55)

Topical NSAIDs Knee 100 Ia 0.44 (0.27, 0.62)

Topical capsaicin Knee 75 Ia 4 (3, 5)

Opioids Any 100 Ia 0.78 (0.59, 0.98)

IA corticosteroid Knee 100 Ia 0.58 (0.34, 0.75) 5 (3, 38)

IAHA Knee 100 Ia 0.60 (0.37, 0.83) 7 (3, 119)

Glucosamine sulphate Both 100 Ia 0.58 (0.30, 0.87) 5 (4, 7)

Glucosamine hydrochloride

Knee – Ib -0.02 (-0.15, 0.11

Chondroitin sulphate Knee 100 Ia 0.75 (0.50, 1.01) 5 (4, 7)

Diacerhein Both – Ib 0.24 (0.08, 0.39)

ASU Both 100 Ia 0.38 (0.01, 0.76) 6 (4, 21)

Rosehip Both 100 Ia 0.37 (0.13, 0.60) 6 (4, 13)

SAM-e Knee 100 Ia 0.22 (-0.25, 0.69)

Surgical

Lavage/debridement Knee – Ib 0.21 (-0.12, 0.54)

Patellar resurfacing Knee 100 Ib 9 (5, 25)

Osteotomy Knee 100 Ia Head to head comparisons, no placebo or conservative therapy controlled trials. HTO improves pain and Similar function improvement as TKR or HTO, but less complications and revision than HTO

Unicompartment knee arthroplasty

Knee 75 SR cohort

Similar function improvement as TKR or HTO, but less complications and revision than HTO

TJR Both 100 III TJR is effective to improve QoL, more beneficial for hip OA from an SR of cohort studies

Abbreviations: ASU: avocado soybean unsponifiables; EMG: electromyography HTO: high tibial osteotomy; IA: intra–articular; IAHA: intra–articular hyaluronic acid; LoE: level of evidence; SAM-e: S-adenosylmethionine; SR: systematic review; TENS: trans cutaneous electrical nerve stimulation; TKR: total knee replacement; NNT: number needed to treat; NS: not significant; TJR: total joint replacement. Ia: Meta–analysis of RCTs; Ib: RCT; IIa controlled study without randomisation; IIb: quasi-experimental study (e.g., uncontrolled trial, one arm dose–response trial, etc.); III: observational studies (e.g., case–control, cohort, cross-sectional studies); IV: expert opinion. QoS (highest quality of study) was assessed using validated scales, e.g., the Oxman and Guyatt scale for systematic review and the Jadad’s scale for clinical trials. The percentage score was calculated for each study. The best available evidence was presented, i.e., SR with the highest quality, RCT with highest quality followed by uncontrolled or quasi experiment, cohort and case–control study. ES = 0.2 is considered small, ES =0.5 is moderate, and ES > 0.8 is large; NNT for symptom relief, unless otherwise specified.


These treatments (with the possible exception of glucosamine sulphate and

chondroitin) are not disease modifying. Therefore, they provide symptomatic

relief, but do not change the disease process.

The most effective of the non–pharmacological therapies are exercise,

thermal therapies (spa / heat / ice) and acupuncture. Paracetamol has a very

small effect size (0.14), while NSAIDs and COX-2 inhibitors have small effect

sizes (0.29 and 0.44). Opioids and corticosteroids have large effect sizes

(0.78 and 0.75), but overall the effect sizes for pain are well below the level of

pain relief desired by patients. Therefore, there remains considerable scope

for additional therapeutic modalities for pain relief from musculoskeletal pain.


1.5.2 Evidence for side effects of pain treatments

Pharmacological therapies have benefits, but they also have side effects

associated with their use. These are summarised in Table 1.3, with

references in the original text (Zhang, 2010).

Table 1.3: Side effects associated with pharmacological therapies. Adapted from Zhang, 2010

Intervention Adverse events RR/OR (95% CI) Evidence

Acetaminophen GI discomfort 0.80 (0.27, 2.37) Meta-RCTs

(paracetamol) GI perforation/bleed 3.60 (2.60, 5.10) CC

GI bleeding 1.20 (0.80, 1.70) Meta-CCs

GI hospitalisation 1.20 (1.03, 1.40) CS

Renal failure 0.83 (0.50, 1.39) CS

Renal failure 2.50 (1.70, 3.60) CC

NSAIDs GI perforation/ulcer/bleed 5.36 (1.79, 16.10) Meta-RCTs

GI perforation/ulcer/bleed 2.70 (2.10, 3.50) Meta-CSs

GI perforation/ulcer/bleed 3.00 (2.50, 3.70) Meta-CCs

GI hospitalisation 1.63 (1.44, 1.85) CS

Myocardial infarction 1.09 (1.02, 1.15) Meta-CSs

Topical NSAIDs GI events 0.81 (0.43, 1.56) Meta-RCTs

GI bleed/perforation 1.45 (0.84, 2.50) Case–control

Serious GI complications 0.33 (0.01, 8.14) Meta-RCTs

Symptomatic ulcers 0.33 (0.01, 8.14) Meta-RCTs

Serious CV or renal events

0.53 (0.08, 3.46) Meta-RCTs

NSAID +PPI vs Serious GI complications 0.46 (0.07, 2.92) Meta-RCTs

NSAID Symptomatic ulcers 0.09 (0.02, 0.47) Meta-RCTs


0.78 (0.10, 6.26) Meta-RCTs

Cox-2 inhibitors +PPI vs Cox-2

Recurrent ulcer bleeding 8.9% vs 0% RCT

inhibitors GI hospitalisation 0.69 (0.52, 0.93) CS

NSAID Serous GI complications 0.57 (0.36, 0.91) Meta-RCTs

+misoprostol Symptomatic ulcers 0.36 (0.20, 0.67) Meta-RCTs

vs NSAID Serious CV or renal events

1.78 (0.26, 12.07) Meta-RCTs

Diarrhoea 1.81 (1.52, 2.61) Meta-RCTs

(Table continues on the next page)


Table 1.3: Side effects associated with pharmacological therapies. Adapted from Zhang, 2010 (cont.)

Intervention Adverse events RR/OR (95% CI) Evidence

Cox-2 inhibitors

Coxibs vs NSAID Serious GI complications 0.55 (0.38, 0.80) Meta-RCTs

Symptomatic ulcers 0.49 (0.38, 0.62) Meta-RCTs


1.19 (0.80, 1.75) Meta-RCTs

Celecoxib Myocardial infarction 2.26 (1.00, 5.10) Meta-RCTs

Myocardial infarction 0.97 (0.86, 1.08) Meta-CSs/CCs

Rofecoxib Myocardial infarction 2.24 (1.24, 4.02) Meta-RCTs

Myocardial infarction 1.27 (1.12, 1.44) Meta-CSs/CCs

Valdecoxib CV events 2.30 (1.10, 4.70) Meta-RCTs

Opioids Any 1.40 (1.30, 1.60) Meta-RCTs

Constipation 4.08 (3.30, 5.05) Meta-RCTs

Nausea 3.15 (2.68, 3.72) Meta-RCTs

Vomiting 5.99 (4.20, 8.54) Meta-RCTs

Dizziness 3.74 (3.00, 4.66) Meta-RCTs

Somnolence 4.78 (3.65, 6.26) Meta-RCTs

Glucosamine Any 0.97 (0.88, 1.08) Meta-RCTs

Chondroitin sulphate Any 0.99 (0.76, 1.31) Meta-RCTs

Diacerhein Diarrhoea 3.51 (2.55, 4.83) Meta-RCTs

IAHA Local adverse events 1.49 (1.21, 1.83) Meta-RCTs

IA high molecular HA (Hylan)

Flares of pain and swelling 2.04 (1.18, 3.53) Meta-RCTs

Abbreviations: CC: case–control study; CS: cohort study; PPI: proton pump inhibitor; H2-blockers: histamine type 2 receptor antagonists; CV: cardiovascular; IA: intra–articular. Table 1.3 has been reprinted from Osteoarthritis Cartilage, Vol 18, Zhang W et al. OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009, pg 476-99., Copyright (2010), with permission from Elsevier.

Overall, the effects of agents used to treat OA vary, from small to moderate.

Many of the pharmacological therapies have increased risk of side effects

associated with their use, and some of the side effects are serious, while

most of the therapies listed in Table 1.2 are not disease–modifying.

Therefore there is enormous scope for the development of additional

effective therapies for OA, especially those which also modify structural

progression.


1.5.3 Emerging bone–active treatments for musculoskeletal pain

New treatments are emerging for musculoskeletal pain using anti–resorptive

bone agents. These have been reviewed briefly by Zhang (2010), but the

field is moving quickly and numerous relevant studies post–date Zhang’s

review.

Interest in the field followed Carbone’s (2004) observational study regarding

the effect of various antiresorptive drugs (oestrogen, raloxifene, and

alendronate) on structural findings and symptoms of knee OA amongst

postmenopausal women (Carbone, 2004). They found that BMLs were

significantly less common in alendronate users (OR 0.11; p≤0.05) compared

to women not using any anti–resorptive agents.

Table 1.4 on page 60 shows experimental studies that investigated the effect

of a bisphosphonate use on participants with OA and displays pain and

structural outcomes (other outcomes not shown). Study quality, site of joint

pain, duration of follow up and outcomes studied vary; few studies

specifically investigated the effect of bisphosphonates on structural outcomes

as well as pain. There is variation between the effect of different

bisphosphonates on pain and structure; therefore beneficial effects may be

limited to some bisphosphonates rather than being a class effect.

Risedronate is the medication studied in the largest number of patients in

good quality trials (Table 1.4). Risedronate (15 mg daily) reduced markers of

cartilage degradation and bone resorption, but differences in pain,

radiological JSN, JSW or osteophyte formation were not statistically

significant (Spector, 2005; Bingham, 2006). Other work demonstrated that

risedronate 50 mg weekly may prevent an increase in BML size over 24

months (Raynauld, 2008) although this did not reach statistical significance.


Alendronate use had no effect on WOMAC outcomes after six months, and

this study did not assess any structural outcomes (Jokar, 2010), and

Fujita (2009) found no difference between the alendronate arm and

participants receiving calcium alone. However, there are data suggesting it

retards spinal osteophyte progression (Neogi, 2008). Fujita (2009) identified

beneficial effects of etidronate compared to the calcium only group, but did

not have any structural endpoints.

Aside from bisphosphonates, there have been several studies with OA

endpoints using other medicines with well–described effects in bone, but

without clear structure modification targets eg BMLs. There are open–label

studies, such as one trial for treatment of knee OA with calcitonin (Esenyel,

2012). Two double–blind, placebo–controlled RCT’s studies have assessed

the effect of strontium; one in spine OA (Bruyere, 2008) and one in knee

OA (Reginster, 2012). Bruyere (123) (124) (124) demonstrated that

strontium was effective in improving back pain (using a 5 point Likert scale)

and reducing disc space narrowing compared to placebo (Bruyere, 2008). A

similar trial has been completed in knee OA, demonstrating statistically

significant reductions in structural and pain endpoints, with reduction in knee

JSN of 0.10mm (2g/day group), proportion of radiological progressors,

markers of cartilage breakdown and WOMAC pain scale (3 units) compared

to placebo over three years. Observed reductions in VAS of 3.01mm

(2g/day) did not quite reach statistical significance. Importantly, this result is

well below the reductions required for clinically significant reductions of pain

(15mm), and persistence of patients to the three year endpoint was poor

(58%) (Reginster, 2012), indicating the difficulty of maintaining patients on


treatment regimens over long periods of time, and the possibility of bias in

the study.

These agents have all been licensed for use for other indications for some

time, and the side–effect profiles observed in these studies were consistent

with those recorded in previous studies (Bruyere, 2008; Reginster, 2012;

Jokar, 2010; Spector, 2005; Bingham, 2006).

Therefore, the use of bone–active pharmacological agents for treatment of

pain in OA and also structural modification is an exciting development in the

field.

Table 1.4: Experimental studies of bisphosphonates in patients with osteoarthritis, sorted by site and year of publication

Study Intervention and dose

vs Population Site Study design

Placebo Sample size

Duration Pain outcomes Structural outcomes

Saviola (2012)

Clodronate 300mg IV

Hydroxy–chlorquine 400mg loading dose, 200mg at 3 months

Erosive hand OA, VAS pain ≥4/10, aged 45-75

Hand RCT (open label)

No 38 24 months

VAS p=0.03 after 3 months

–

Spector (2005)

Risedronate 5mg/day; 15mg/day

Placebo ACR–defined knee OA, daily knee pain, aged 40–80

Knee RCT Yes 284 12 months

WOMAC (ns) JSN (p=0.28)

Bingham (2006)

Risedronate 5mg/day; 15mg/day; 50mg/week

Placebo ACR–defined knee OA, knee pain on most days, medio-tibial mJSW 2–4 mm, aged 40–80


WOMAC p=0.66

JSW (p=0.98)

Kawasaki (2008)

Risedronate (2.5mg/day + exercise)

Glucosamine + exercise vs exercise alone

ACR–defined knee OA, post–menopausal women

Knee RCT (open label)

No 142 18 months

WOMAC (ns), VAS (ns)§

JSW (ns)§

Rossini (2009)

Clodronate (IA) 0.5 mg/week; 1mg/week; 2 mg/week, 2 x 1mg/week

Hyaluronic acid (20mg / week)

ACR–defined knee OA, KL grades 2–3, symptoms ≥3 months

Knee RCT (open label)

No 145 5 weeks VAS (ns) –

Jokar (2010)

Alendronate 70 mg weekly

Placebo ACR–defined knee OA, WOMAC pain score 2/5 & daily knee pain for ≥6mo.


WOMAC p= 0.94

–

Table continues on next page

Table 1.4: Experimental studies of bisphosphonates in patients with osteoarthritis, sorted by site and year of publication (cont.)

Study Intervention and dose

vs Population Site Study design

Placebo Sample size

Duration Pain outcomes Structural outcomes

Fujita (2001)

Etidronate 66 mg/day; 133 mg/day; 200 mg/day

No treatment Back and/or knee pain due to spondylosis deformans and/or knee OA

Knee, spine

RCT, strati–fied by age, disease severity

No 80 12 months

VRS p<0.001; skin impedence p<0.001 between no treatment and all doses

-

Fujita (2009)

Alendronate 5 mg/day; etidronate 200 mg/day (ave.) risedronate 2.5 mg/day + calcium

Calcium alone 900 mg/day, for 7 months

Back or knee pain Knee, spine

RCT No 199 7 months

VRS, skin impedence p<0.001 between etidronate and calcium alone, others ns.

–

Results listed as not significant (ns) if paper does not state p value. JSN: joint space narrowing; JSW: joint space width §Comparison is for risedronate vs exercise alone VRS: Visual rating scale KL grade: Radiographic criteria for assessment of osteoarthritis using the Kellgren and Lawrence (KL) grading system IA: intra–articular ave: average


1.6 Summary

Arthritis is the most common cause of chronic pain in older people, affecting

more than 6.3 million Australians. The most recent estimates suggest that

arthritis and musculoskeletal conditions constituted the fourth largest

component of direct health expenditure, costing the Australian economy

AUD$4.0 billion annually.

Correlates of pain are not consistent across all joints, but include obesity,

weak muscles, pain in other joints and numerous structures visible on MR

imaging, including bone marrow lesions, cartilage defects, meniscal tears,

osteophytes (but not independently of MRI changes), joint effusions, and

synovitis. Features visible only on radiographs (eg joint space narrowing) are

poorly correlated with pain. Cognitive, psychological, and psychosocial

aspects also influence pain, with causality also working in the opposite

direction, with evidence that osteoarthritic knee or hip pain determines

subsequent depressed mood through its effect on fatigue and disability.

Treatment options for modifying musculoskeletal pain include non–

pharmacological treatments, such as weight loss, physical activity, and

lifestyle modification. Pharmaceutical treatments include oral paracetamol,

NSAIDs, COX–2 inhibitors, glucosamine sulphate, chondroitin sulphate,

capsaicin, injections of corticosteroids, glucosamine, chondroitin sulphate,

and weak opioids. Once conservative measures have failed, surgical

treatments such as joint replacements may be considered. The effect of

treatment from available therapies remains suboptimal, and although existing

treatments are safe options, all pharmacological and surgical treatments

have side effects and risks. There is scope in the current treatment


armamentarium for more effective therapies, and even for treatments with

smaller effect sizes that can be taken in addition to existing medications as

long as they are safe. Treatments remain symptom modifying but not truly

disease modifying. An agent that achieves symptom modification and

disease modification remains the “holy grail” for OA treatment.

Chapter 2: Research questions



Chapter 2. Research questions

2.1 Research questions

Research questions 1 and 2 investigate correlates and one determinant of

musculoskeletal pain.

In a population-based cohort of community-dwelling adults aged 50–80 years

examined at baseline and 2.6 and 5 years later:

1. What is the relationship between osteoarthritis and health–related QoL

over five years?

1.1. Is the relationship between these factors the same cross–sectionally

as it is longitudinally (over 2.6 and five years)?

1.2. What is the contribution of physician diagnosed OA, radiographic

measures of knee OA and pain at multiple sites to QoL?

2. Is there an association between baseline 25-hydroxyvitamin D (25–OHD)

at baseline, and change in knee pain over 5 years and change in hip pain

over 2.6 years, as measured by the Western Ontario and McMaster

University Osteoarthritis Index (WOMAC) questionnaire?

2.1. If there is an association, what is the nature of that association? Is

the association linear or is there a threshold?

2.2. Is the relationship consistent within WOMAC subscales?


Research questions 3 and 4 investigate modifiers of musculoskeletal pain

using two different treatment modalities in double–blind randomised–

controlled–trials.

3. Is a thrice daily application of topical 4Jointz 3.5 g/day (compared to

placebo), effective in reducing knee pain, improving muscle strength and

markers of inflammation and cartilage breakdown over twelve weeks in

participants aged >50 with OA and a pain intensity score >40mm on a

visual analogue scale (VAS)?

3.1. Does this effect reverse over four weeks after discontinuation of

4Jointz (compared to placebo)?

4. Is a single infusion of zoledronic acid 5mg (compared to placebo)

effective in reducing knee pain and BMLs over twelve months in

participants aged ≥50 years with ACR–defined clinical knee OA, pain on

most days and a pain intensity score of >40mm on a visual analogue

scale (VAS) and a prevalent knee BML?

4.1. If there is a reduction in areal BML size, is it sufficient to expect that

this is the mechanism for the pain reduction?

Chapter 3: Methodology



Chapter 3. Methodology

3.1 Prelude

Two chapters of this thesis utilise data from the Tasmanian Older Adult

Cohort (TasOAC) study. This chapter describes the study design, study

population, and measurement protocols which are common to these two

chapters.

Please note that the following data chapters are presented in the form in

which they were accepted by, or submitted to peer–reviewed scientific

journals. Therefore there are some differences in the way aspects of the

TASOAC study are described, based on requirements of different journals

and the emphases required for different analyses. The sample sizes used in

individual chapters varies for each of the research questions.

Chapters 6 and 7 describe the two intervention trials of this thesis – 4Jointz

and ZAP. These are both placebo–controlled double–blind randomised

controlled trials in patients with clinical knee OA. Study–specific

methodologies for these two trials appear in these two chapters.

3.2 TASOAC design and study population

TASOAC is an ongoing prospective, population–based study which aimed to

identify the environmental, genetic and biochemical factors associated with

the development and progression of osteoarthritis (OA) and osteoporosis at

multiple sites (hand, knee, hip, spine).

The TASOAC sample consists of men and women aged 50-80 years (mean

age 62±7 years), selected from the roll of electors in southern Tasmania

(population 229,000) using stratified simple random sampling without

replacement. Stratification was by sex, enabling equal numbers of men and


women to be enrolled. The electoral roll represents the most complete

population listing of Australian adults available, as voting is compulsory in

state and federal elections. As TasOAC was designed to examine

community–dwelling older adults, institutionalised older adults were excluded

from the initial sample. Participants were also excluded if they had contra–

indications for MRI (including pacemakers, implants and claustrophobia), as

MRI was required to examine OA progression. Other exclusion criteria

included body weight exceeding the weight limit on the dual energy X–ray

absorptiometry (DXA) machine (>135 kg), and inability to come to the clinic

(for example, if they resided interstate or overseas, see Figure 3.1).

3.2.1 Ethics

The Southern Tasmanian Health and Medical Human Research Ethics

Committee approved the study (Ethics Approval Number: H6488), and we

obtained written informed consent from all participants.

3.2.2 Baseline (Phase 1)

An overview of participant recruitment and withdrawal during the baseline

phase of TASOAC is shown in Figure 3.1. 2530 people were identified from

the electoral roll, of which 2135 were identified as initially eligible. Of the

people who did not take part in the study, 395 people were identified as not

being eligible, with the most common reasons being claustrophobia, too sick,

or living overseas or interstate. 231 people were not able to be contacted,

804 did not want to enter the study, and one participant failed to attend the

clinic. The remaining 1099 people attended the clinic at the Menzies

Research Institute Tasmania from February 2002 to September 2004.

The overall response rate for participation in Phase 1 is 57%, which is similar

to response rates from studies with equivalent response burdens conducted


around the same time period, such as the North West Adelaide Health Study

at 58% (Grant, 2009), and the Australian Diabetes, Obesity and Lifestyle

Study at 52% (Dunstan, 2002).

Figure 3.1 provides an overview of participant recruitment into Phase 1.

Participants in TASOAC completed questionnaires on a wide range of

demographic factors, as well as a number of specific questionnaires including

knee pain and stiffness and quality of life. Participants also attended clinic at

the Menzies Research Institute Tasmania and supplied a fasting blood

sample, and had other measures taken in person, such as blood pressure

and leg strength. Participants also attended appointments for bone density

testing (using dual energy X–ray absorptiometry (DXA)), radiography, and

magnetic resonance imaging).


Figure 3.1: Flow chart of TasOAC recruitment and participation to end of Phase 1

Initially Ineligible N=395 Age ≥ 80 47 Deceased 31 Too sick 50 Living overseas or interstate 53 Suffered a Stroke 11 Dementia 19 Hip/Knee Replacement 39 >135kgs 11 Nursing Home 16 P/maker or implant 15 Language Problems 15 Claustrophobia 88

Total persons identified from electoral roll

n = 2530

Not contacted after multiple attempts n=177 Uncontactable n=54 (n=231)

Refused n=805

Response rate = 1099/(2135-231)=57%

Participation rate = 1099/2135=51.5%

994 participants had baseline MRI 105 participants had no baseline MRI

Initially eligible n=2135

Participated n = 1099

Failed to attend clinic n=1


Table 3.1 shows that TASOAC participants (n=1099) were representative of

the 2530 people selected from the electoral roll with regard to sex, (48.9 %

male vs 50.7% male), and also regard to age for the middle and younger

third of the cohort (born 1933 – 1945 and 1943 – 1952). However, the older

age group (born 1921 – 1933) were under–represented in the 1099

participants who provided baseline measures (21.4% vs 39.8% and 35.9%

for the younger groups).

Table 3.1: Baseline demographic characteristics of those participants who completed Phase 1 (n=1099) and those who did not (n=1431)

Did not participate in Phase 1

Participated in Phase 1

n=1431 n=1099 p

Sex (% Male) 50.7 48.9 0.37

Age group

1921-1933 486 (34.0) 235 (21.4) <0.001

1933-1945 473 (33.1) 437 (39.8)

1943-1952 423 (29.6) 394 (35.9)

Age group 1921 - 1933 consists of persons in the age groups "1921-1925" "1923-1927" "1925-1929" "1928-1932" and "1929-1933". Age group "1933 - 1945" consists of persons in the age groups "1933-1937" "1937-1941" "1938-1942" and "1941-1945". Age group "1942 - 1952" consists of persons in the age groups "1943-1947" "1945-1949" "1948-1952".

3.2.3 2.6 year follow up (Phase 2)

Participants were contacted and asked to return for subsequent visits after 2–

3 years (mean ± SD 2.6 ± 0.4; range 1.4–4.8 years). The majority of the

1099 participants who took part in Phase 1 returned for Phase 2 (80%, see

Figure 3.2). As TASOAC aimed to measure osteoarthritis progression,

participants without baseline MRI were excluded from Phase 2. The other

common reasons for patients discontinuing involvement in the study after

Phase 1 were not wanting to continue in the study.


Figure 3.2: Flow chart describing participation in Phase 2 of TASOAC

Ineligible n=162

n

No MRI 84

Deceased 16

Moved interstate or overseas 14

Moved to nursing home 1

Joint replacement 15

Physically unable 16

Other reasons 16

Refused to continue n=58

Unable to trace n=4

Eligible subjects for Phase 2 n = 1099

Participation rate = 875/1099=80%

Phase 2 Participants n=875 (1099-224 withdrawals)


TASOAC participants who did not complete Phase 2 were older, more likely

to be female, shorter and had higher BMI than participants who completed

both Phase 1 and Phase 2 (Table 3.2).

Table 3.2: Baseline demographic characteristics of those participants who completed Phase 2 (n=875) and those who did not (n=224)

Participated in Phase 2 (n=875)

Did not participate in Phase 2 (n=224)

p value

Age (years) 62.7 (7.3) 64.4 (8.2) <0.01 Male sex (n, %) 445 (51) 92 (41) <0.01 Height (cm) 167.5 (9.0) 164.9 (8.8) <0.01 Weight (kg) 77.9 (14.6) 77.7 (16.5) 0.824 BMI (kg/m2) 27.7 (4.6) 28.5 (5.7) 0.040

Bolded results indicate statistically significant difference at =0.05 *Mean (standard deviation) except for percentages. P values determined by t–test or chi–square test (where appropriate). BMI: body mass index.


3.2.4 Five year follow up (Phase 3)

Participants who completed Phase 2 were invited to continue participation in

the study for Phase 3, which occurred 5 years after Phase 1 (mean ± SD

5.05 ± 0.5; range 3.6 – 6.9 years).

The most common reasons for patients to discontinue involvement in the

study after Phase 2 were refusing to continue, physical inability to attend, and

death (see Figure 3.3).

Figure 3.3: Flow chart describing participation in Phase 3 of TASOAC

Withdrawal reason n=70 n

No MRI 0 Deceased 19 Moved interstate or overseas 12 Moved to nursing home 6 Joint replacement 1 Unable to trace 3 Physically unable 23 Willing but unable to attend 3 Not contacted 2

Other reasons 1

Refused to continue 36

Eligible subjects for Phase 3 N = 875

Participation rate = 769/875=87.9%

Phase 3 Participants N=769 (875-106 withdrawals)


Those completing Phase 3 were younger, taller and had lower BMI at

baseline than participants who did not complete Phase 3 (Table 3.3). This

includes participants who dropped out before Phase 2.

Table 3.3: Characteristics of study cohort at baseline in participants who did and did not complete Phase 3

Participated in Phase 3

Did not participate in Phase 3

Mean (sd) Mean (sd) p

n=769 n=330 value

Age (years) 62.1 (7.0) 65.2 (8.1) <0.001

Sex (% male) 49.5 54.8 0.110

Height 167.5 (8.9) 165.7 (9.2) 0.003

Weight 77.8 (14.6) 78.1 (15.8) 0.747

Body mass index 27.7 (4.6) 28.4 (5.1) 0.02

Bolded results indicate statistically significant difference at =0.05 *Mean (standard deviation) except for percentages. P values determined by t–test or chi–square test (where appropriate). BMI: body mass index.


3.3 Measurement of pain

Functional MRI (fMRI) is an MRI procedure that measures brain activity by

detecting associated changes in blood flow. fMRI scans show altered

processing of the affective qualities of the ongoing pain (Baliki, 2008;

Kulkarni, 2007; Parks, 2011), and should give the actual pain patients

experience (as compared to what they report), as well as answering

important questions about the nature of pain in patients with osteoarthritis.

Therefore, this represents the gold standard of pain measurement in an ideal

world, but fMRI and other brain imaging techniques are limited to specialised

use and are not currently used as outcome measures in clinical trials or

epidemiological studies.

Pain questionnaires and visual analog scales are the usual methods of

assessing pain intensity due to good reliability, validity, sensitivity to change

and ease of use, but the potential for under– or over–reporting of pain

intensity remains. This may be systematic in nature, and so this limitation

needs to be considered in data interpretation.

Questionnaire–based methods of assessing musculoskeletal pain in adults

can be divided into several categories (Hawker, 2011). These include:

generic unidimensional pain questionnaires (visual analog scale and

numeric rating scale);

generic multidimensional pain questionnaires (Short Form–36 Bodily

Pain Scale);

arthritis–specific pain questionnaires (Measure of Intermittent and

Constant Osteoarthritis Pain) (Hawker, 2008); and


composite measures of arthritis symptoms, including pain and

associated disability or dysfunction, such as the Western Ontario and

the Knee Injury and Osteoarthritis Outcome Score (KOOS) (Roos,

1998) and McMaster Universities Osteoarthritis Index (Bellamy, 1988).

In this thesis, we have used visual analog scales, WOMAC and KOOS

questionnaires to assess pain intensity.


3.4 Study populations

Participants from TASOAC are utilised in two chapters – Chapter 4 and

Chapter 5. A summary of when measures were assessed over all three

Phases is shown in Table 3.4 on page 89. This is not an exhaustive list of all

the measures which were actually taken in TASOAC.

Chapter 6 and Chapter 7 utilise study participants recruited into the 4Jointz

and ZAP trials rather than TASOAC. Characteristics of the study participants

are presented in each of these chapters.

Study populations are summarised in Table 3.6 on page 91.

3.5 Study measures

Details of how outcome measures and covariates were assessed are

described below. Study measures appear here in Chapter 3 if they were

used in multiple studies or where space restrictions precluded full description

of methods in published papers. The location of methods descriptions for

particular outcomes, predictors or covariates are shown in Table 3.5 on page

90.

3.5.1 Anthropometrics

Body weight was measured to the nearest 0.1 kg (with shoes, socks, and

bulky clothing removed) using a single pair of electronic scales (Seca Delta

Model 707, Bradford, MA, USA). Height was measured to the nearest 0.1 cm

(with shoes and socks removed) using a stadiometer. Body mass index

(BMI) was calculated as weight (kg)/ (height (m))2. Waist and hip

circumference were measured to the nearest 0.1 cm using a constant tension

tape (Figure Finder Tape Measure) directly over the skin.


3.5.2 Questionnaire measures

3.5.3.1 Highest educational attainment

At baseline, participants were asked “What is the highest qualification you

have completed?”. Participants could select one answer only. Response

options are as follows: “No formal qualifications”; “School or Intermediate

certificate (or equivalent)”; “Higher School or Leaving Certificate (or

equivalent)”; “Trade/apprenticeship (eg Hairdresser, Chef, Motor Mechanic)”;

“Certificate/diploma (eg Child Care, Technician, Nursing, Chartered

Accountant)”; “University Degree”; “Higher University degree”.

3.5.3.2 Current employment status

At baseline, participants were asked “Which of the following best describes

the occupation you had for the longest period?”. Response options were as

follows: “Manager or administrator”, “Professional (eg engineer, doctor,

teacher, nurse, police officer, technical officer)”, “Tradesperson (eg

carpenter, electrician, plumber, book keeper, etc)”, “Salesperson or personal

service worker (eg sales rep., teller, insurance rep, real estate rep., etc)”,

“Plant or machine operator, or driver (eg taxi or bus driver, etc)”, “Clerk (eg

typist, receptionist, data processor, bookkeeper, etc)”, “farmer”, “Labourer or

related worker (eg trade assistant, factory hand, agricultural labourer,

construction, mining)”, “Member of armed forces”, or “other”.

3.5.3.3 Self–reported arthritis, as diagnosed by a physician

Participants were asked about presence or absence of physician–diagnosed

osteoarthritis and pain at baseline at the neck, back, hands, shoulders, hips,

knees, or feet (yes / no options – see Appendix 1)), and physician–diagnosed

rheumatoid arthritis (RA) (yes / no).


3.5.3.4 Self reported pain

Similarly, participants were asked whether joint pain was present or absent at

seven different joints: neck, back, hands, shoulders, hips, knees, or feet (see

Appendix 1).

3.5.3.5 Cigarette smoking

Self–reported estimates of smoking status (never, former, and current) was

determined by questionnaire from the following questions “Have you ever

smoked cigarettes on a regular basis?”; “Do you currently smoke

cigarettes?”, and “If you have given up smoking, at what age did you stop?”

(see Appendix 1). Participants were considered a current smoker if they

reported currently being a “regular smoker”.

3.5.3.6 Alcohol consumption

Alcohol consumption was assessed by a validated food frequency

questionnaire (FFQ) which was developed specifically for use in Australian

adults (Hodge, 2000). Participants were asked about their average alcohol

consumption over the past 12 months. The consumption frequency of each

alcohol type [beer (low alcohol); beer (full strength); red wine; white wine

(includes sparkling wines); fortified wines, port, sherry, etc.; and spirits,

liqueurs, etc.] was asked about separately. An estimated daily intake of

alcohol (gram/day) was calculated.

3.5.3.7 Western Ontario McMaster Osteoarthritis Index (WOMAC)

Self–reported knee and hip pain, function and stiffness were assessed by

questionnaire for the last 30 days using the Western Ontario McMaster

Osteoarthritis Index (WOMAC) (Bellamy, 1988) (see Appendix 1). The

WOMAC pain scale has five items, each rated on a 10–point scale from 0 (no

pain) to 9 (most severe pain). Lower scores indicate lower levels of

symptoms or physical disability. Each pain item was summed to create a


total pain (0–45) score. The WOMAC index has good test–retest reliability,

with values of 0.68 for the pain scale and 0.48 for the function

scale (Bellamy, 1988), and has demonstrated convergent construct validity

over numerous impairments (McConnell, 2001). Responsiveness of the

WOMAC is variable depending on the intervention measured (McConnell,

2001), as expected.

3.5.3 Strength and physical activity measures

3.5.3.1 Muscle strength

Leg strength was measured to the nearest kilogram in both legs

simultaneously, using a dynamometer (TTM Muscular Meter, Tokyo, Japan).

Participants stood on the back of the dynamometer platform, with back

straight against a wall and knees flexed to an angle of 115º from the neutral

angle of full extension (dependent on participant range of motion). A

demonstration of the leg strength assessment technique is provided in Figure

3.4. A bar connected by a chain to the dynamometer was held on the front of

the thighs with both hands. Using only their legs and keeping the back and

neck straight, the participant was then instructed to lift the bar upwards with

maximum force, and given verbal encouragement until a maximal contraction

was achieved. This test examines isometric strength of the whole legs, but

predominantly of the quadriceps and hip extensors.

Two trials were recorded, with the mean score taken as the criterion value for

leg strength. A third trial was performed if the score for the first two trials

varied by more than 10% (Kumar, 2004). Intra–class correlation coefficients

(ICC’s) demonstrated high reproducibility between trials 1 and 2 at both

baseline (ICC 0.95, 95% CI 0.94, 0. 96) and follow–up (ICC 0.96, 95% CI

0.95, 0.97).


Figure 3.4. Demonstration of the leg strength test performed in the TASOAC study (from Scott, 2010).

This measure of muscle strength has not been validated, but quadriceps

strength as measured by isokinetic knee extension strength tests used in falls

risk assessment has been previously demonstrated to be a predictor of

pain, (Zhai, 2006) falls (Lord, 1999), disability (McAlindon, 1993) and

mortality (Newman, 2006) using similar tests. Knee extension strength in our

participants at all points was strongly correlated with leg strength (r = 0.77 at

Phase 1, r = 0.73 at Phase 2 and r = 0.73 at Phase 3, all p<0.0001) providing

reassurance about our leg strength measure. We chose not to include knee

extension strength in our analyses due to a “ceiling effect” in that

approximately 20% of participants achieved the maximum reading of 46kg at


each of the three time points, and also because it assesses strength over the

whole leg rather than predominantly the quadriceps.

3.5.3.2 Pedometers

Physical activity levels were assessed as steps per day using pedometers

(Omron HJ–003 and HJ–102; Omron Healthcare, Kyoto, Japan).

Pedometers were calibrated at the clinic with the participant present, using a

100–pace walking test. Participants were shown how to attach the

pedometers to their waistband or belt and were instructed to wear the

pedometer above their dominant leg. Pedometers were calibrated at the

clinic with the participant present, using a 100–pace walking test.

Participants were provided with a pedometer diary and were instructed to

record their steps daily for seven consecutive days from the following day.

Participants were mailed out a second pedometer after a six month period

and repeated the process. A steps per day value was calculated which was

the daily average of these two time periods. The start and the finish times of

pedometer use were recorded on each day, and participants also reported

the duration and the type of physical activity for any periods in which they did

not wear the pedometer. Pedometer readings were excluded if they were

determined to be caused artificially (eg report of work done on heavy

machinery), or if the pedometer had been worn for less than five days and for

less than eight hours on each of these days, excluding reported duration of

pedometer removal.

3.5.4 X–ray

Participants had X–rays of both hips (n=1014) and knees (n=1020) in the

standing anterio–posterior position at baseline only. Knee X–rays were taken

of both knees with 15° of fixed knee flexion, and pelvic radiographs with both


feet in 10° internal rotation. Films were scored individually for osteophytes

and joint space narrowing (JSN) on a scale of 0–3 (where 0=no disease and

3=most severe disease) according to the Osteoarthritis Research Society

International (OARSI) atlas as previously described (Altman, 1995). This is

also referred to as “OARSI grade”. Hips and knees with scores 1–3 at any

site were classified as having JSN or osteophytes. Two readers

simultaneously assessed radiographs with immediate reference to the atlas.

Scores for each participant were determined by consensus. Intraobserver

repeatability was assessed in 40 participants (intraclass correlation

coefficients (ICCs) 0.65 to 0.85 for the knee and 0.60– 0.87 for the

hip) (Foley, 2006).


Table 3.4: Summary of when measures were assessed in the TASOAC study

Note: This is not an exhaustive list of all the measures taken in TASOAC, only the most relevant.

Measure Baseline (Phase 1) n=1099

2.6 years (Phase 2) n=875

5 years (Phase 3) n=769

Questionnaire items Occupation

Employment status

WOMAC scale Knee pain

Hip pain

Pain at any of these sites – neck, back, hands, shoulders, hips, knees, feet,

Osteoarthritis diagnosed by a doctor (y/n) at neck, back, hands, shoulders, hips, knees, feet

Smoking survey

Ever been diagnosed by a doctor (y/n) with rheumatoid arthritis

Current medications (dosage, frequency) including prescription and over the counter medications

Dietary questionnaire (FFQ), including alcohol intake

AQOL

Clinic measurements Blood taken (vitamin D)

Height, weight, girth (hip and waist)

Pedometer (7 days of wear at 2 time points 6 months apart)

Leg strength

X-ray Hip

Knees

MRI Knee

(n=425)

Hip

(n=151)

(n=323) (n=220)


3.6 Summary of outcome factors, study factors, and covariates

Table 3.5 summarises the variables used in each chapter of this thesis.

Table 3.5: Summary of outcome factors, study factors, and covariates used in this thesis

Chapter Outcome factors Study factors Covariates

4 Quality of life (AQoL)*

Self–reported physician–diagnosed osteoarthritis, self–reported joint pain (yes / no), knee osteophytes, knee joint space narrowing

Self–reported physician diagnosed rheumatoid arthritis, leg strength, age, sex, BMI

5 Serum 25-OHD (Vitamin D)*

WOMAC knee and hip pain

Age, sex, BMI, season, leg strength, hip joint space narrowing, osteophytes, number of cartilage defects, presence of knee bone marrow lesions

6 Knee pain (VAS)*, KOOS pain scale; knee function*; IL–6*, CTX–2*, OMERACT–OARSI response criteria*; paracetamol use*; leg strength; adverse events*

Randomised to receive 4Jointz or placebo

OARSI grade, sex

7 Knee pain (VAS)*, KOOS pain scale*; bone marrow lesion size*, adverse events*

Randomised to receive zoledronic acid or placebo

Age, sex, baseline pain score, baseline pain medicine use

*Measurement protocol described in “Methods” or “Patients and Methods” section of relevant chapter. AQoL: Assessment of Quality of Life instrument OARSI grade: a classification of radiographic knee osteoarthritis VAS: visual analog scale IL-6: interleukin 6, an inflammatory marker CTX-2: C–terminal cross linking telopeptide of type 2 collagen, a marker of cartilage tissue degredation OARSI–OMERACT response critieria: responder criteria defined by the relevant professional societies KOOS: Knee Injury and Osteoarthritis Outcome Score

Table 3.6. Study populations used in this thesis

Chapter Study Selection Source Recruitment location

Population Year of data collection

Age† n

4,5 Tasmanian Older Adult Cohort Study (TASOAC)

Random selection

Electoral roll Southern Tasmania

Ambulant community dwelling

2002–08 50–80 P1:1099 P2: 875 P3: 769

6 A randomised controlled trial of Arthritis Relief Plus for osteoarthritis of the knee (4Jointz trial)

Convenience sample

Newspaper advertising, physician referral

Southern Tasmania, Sydney

Clinical knee OA, Knee pain on most days, VAS pain score ≥40 mm

2011 >50 133

7 Zoledronic acid in knee pain associated with bone marrow oedema (ZAP trial)

Convenience sample

Newspaper advertising, physician referral

Southern Tasmania

Clinical knee OA, Knee pain on most days, VAS pain score ≥40 mm, bone marrow lesion

2009–10 >50 59

†Age (years) at enrolment VAS: visual analog score P1, P2, P3: The three phases of TASOAC, phases 1, 2 and 3, representing baseline, 2.6 year follow up and 5 year follow up


3.7 Statistical analysis

T-tests and 2 tests were used to compare differences in means and

proportions as appropriate. Statistical significance was determined using

=0.05 and two –tailed tests throughout the thesis. Detailed descriptions of

statistical analyses performed are presented in the relevant data chapters.

All statistical analyses were performed on Stata 10 – 12 for Windows

(StataCorp, College Station TX, USA).

Chapter 4: Musculoskeletal pain and quality of life

Chapter 4: A prospective study of the impact of musculoskeletal pain and

radiographic osteoarthritis on health related quality of life in community dwelling older

people


Chapter 4. A prospective study of the impact of

musculoskeletal pain and radiographic osteoarthritis

on health related quality of life in community

dwelling older people

This manuscript has been published (Laslett et al BMC Musculoskelet Disord.

2012;13:168). The typeset version of the manuscript as it appeared in the

journal is in Appendix 4.

The text of this chapter is the same as the published version, except where

changes have been requested by the examiners. Therefore there is some

repetition of the methods, some of which appear in more detail in Chapter 3.

4.1 Introduction

Quality of life (QoL) is a useful and widely–used measure of health status

because it captures the personal and social context of patients’ lives in a

quantifiable way, and predicts use of health care resources and mortality (Dorr,

2006; Singh, 2005). Osteoarthritis (OA) is a leading cause of disability amongst

older adults, and persons with osteoarthritis typically score poorly on QoL

measures. Aspects of QoL involving physical functioning and pain are the most

affected, and patients who report pain typically report it at more than one

site (Croft, 2005). Number of sites of pain have been associated with

increasing disability (Croft, 2005) and poorer overall health, sleep quality and

psychological health (Kamaleri, 2008). However, it is unclear whether pain at

different sites is additive in terms of effect on QoL. Radiographic markers of

osteoarthritis are weakly associated with pain (Bedson and Croft, 2008;

Hannan, 2000) but both are associated with poor QoL, and it is unclear if

radiographic findings are independent of a diagnosis of OA, or pain (Kim, 2010;


Muraki, 2011; Norimatsu, 2011). In addition, it is not known whether the cross–

sectional associations track over time. Baseline back, knee and hip pain were

associated with reducing QoL over four years of observation in a Chinese

volunteer cohort (Woo, 2009) but this has not been reported in western

populations, in other anatomical sites, or in a population which also has

radiographic measures.

The aim of this study was to describe the association between osteoarthritis and

QoL in a community dwelling population–based sample of older people over five

years.

4.2 Patients and methods

4.2.1 Participants

The Tasmanian Older Adult Cohort (TASOAC) is an ongoing, prospective,

population–based study examining the determinants of osteoarthritis and

osteoporosis in older community dwelling adults. Men and women aged 50–80

years in 2002 were selected from the electoral roll in Southern Tasmania

(population 229,000) using sex–stratified simple random sampling without

replacement (response rate 57%). Participants were excluded if they resided in

an aged care facility. The research was approved by the Southern Tasmanian

Health and Medical Human Research Ethics Committee and written informed

consent was obtained from all participants. Participants attended clinic and

completed questionnaires. Data collection included blood sampling, magnetic

resonance (MR) imaging (not reported in this study), knee and hip X–ray and

other correlates of knee and hip OA and osteoporosis. Baseline data (Phase 1)

was collected from February 2002 to September 2004. Follow up data (Phase

2 and 3) was collected on average 2.6 (range 1.4 to 4.8) and 5 years (range 3.6

to 6.9 years) later. Participants who did not have an MRI at Phase 1 (n= 105)


were excluded from further participation in the study, as TASOAC aimed to

measure osteoarthritis progression.

4.2.2 Quality of life

Health–related QoL was measured using the Assessment of Quality of Life

(AQoL) questionnaire (Hawthorne, 2000). This is a generic QoL instrument with

five subscales (Illness, Independent Living, Social Relationships, Physical

Senses and Psychological Well–being), each with three items with four

response levels (scored 0–3 for each item). The AQoL is a valid measure of

QoL (Osborne, 2003) and is reliable in population–based settings (Cronbach’s α

= 0.81) (Hawthorne and Osborne, 2005). The AQoL was used as an

unweighted, psychometric instrument providing ‘value’ profiles, rather than

using the utility measures (Hawthorne, 2000) such as the AQoL–4D. These use

only four of the subscales, excluding the Illness subscale which includes

questions about the use and reliance on prescribed medicines or medical aids

and requirement for regular medical treatment, all of which are likely to be

increased by pain or a diagnosis of OA. Total scores for each subscale

therefore ranged from 0–9 and the total instrument 0–45, with higher scores in

each scale indicating worse QoL.

4.2.3 Physician diagnosed osteoarthritis, pain and rheumatoid arthritis

Participants completed questionnaires (n=1099) which asked “Have you had

been told by a doctor that you have osteoarthritis at any of these sites”, and “Do

you experience pain at any of these sites?". The seven anatomical sites were

neck, back, hands, shoulders, hips, knees, and feet. Participants were given

the choice between answering "yes" or "no". Participants were also asked

“Have you been told by a doctor that you have rheumatoid arthritis?” (yes / no).

Questions were asked about pain at Phase 1, 2 and 3; doctor diagnosed OA at

Phase 1 and 2, and about doctor diagnosed RA at Phase 1.


4.2.4 X–ray

Participants had X–rays of both hips (n=1014) and knees (n=1020) in the

standing anterio–posterior (AP) position at baseline only. Knee X–rays were

taken of both knees with 15° of fixed knee flexion, and pelvic radiographs with

both feet in 10° internal rotation. Films were scored individually for osteophytes

and joint space narrowing (JSN) on a scale of 0–3 (where 0=no disease and

3=most severe disease) according to the Osteoarthritis Research Society

International (OARSI) atlas (Altman, 1995) as previously described (Foley,

2006). Hips and knees with scores 1–3 at any site were classified as having

JSN or osteophytes. Two readers simultaneously assessed radiographs with

immediate reference to the atlas. Scores for each participant were determined

by consensus. Intraobserver repeatability was assessed in 40 participants

(intraclass correlation coefficients (ICCs) 0.65 to 0.85 for the knee and 0.60–

0.87 for the hip) (Foley, 2006).

4.2.5 Other factors

Leg strength (n=1038) was measured to the nearest kilogram in both legs

simultaneously, using a dynamometer (TTM Muscular Meter, Tokyo, Japan) as

described in Scott, 2009a (Scott, 2009). This tests isometric strength,

predominantly of the quadriceps and hip extensors. Weight was measured to

the nearest 0.1 kg (with shoes, socks, bulky clothing and headwear removed)

using a single pair of calibrated electronic scales (Seca Delta Model 707).

Height was measured to the nearest 0.1 cm (barefoot) using a stadiometer.

Body mass index (BMI) was calculated [weight (kg)/(height (m))2]. Physical

activity levels were determined using pedometers (Omron HJ–003 & HJ–102;

Omron Healthcare, Kyoto, Japan) as previously described (Scott, 2009).

Briefly, number of steps per day is an average of seven consecutive days and


averaged across two time points in different seasons. We collected self–

reported estimates of current cigarette smoking prevalence by questionnaire.

4.2.6 Data analysis

We used Stata 10.0 (StataCorp LP) for statistical analyses. Statistical

significance was set as a p value ≤0.05 (two–tailed). Sample characteristics

were analysed using t–tests and chi–square tests as appropriate. Analyses

used total AQoL score as the outcome, and diagnosed OA, JSN, osteophytes

and pain as co–predictors. Baseline data was analysed using multiple linear

regression. Analyses were first adjusted for age, sex and body mass index

(BMI) (Step 1); variables which demonstrated a statistically significant

association with total AQoL score were put into the next analysis, with the

confounders leg strength and RA. The purpose of this was to determine

whether each factor was independently associated with QoL or whether they

were no longer significant after adjusting for other factors, suggesting mediation

of effect.

Multilevel mixed–effects linear regression were used for longitudinal analyses,

clustering on ID, and adjusted for change in BMI and age over time, as these

terms were statistically significant. These were intent to treat analyses and

used all available data.

We transformed the total AQoL score using a square root transformation in

order to meet the residual assumptions underlying linear regression.

Regression coefficients were back–transformed, and the β value was reported

for each dependent variable, calculated with all other continuous variables

centred at their mean, and dichotomous variables with the reference group

having a value of zero. As a sensitivity analysis, we re–ran models in Table 3


without the psychological wellbeing scale to assess the possible effects of

psychological distress as an unmeasured confounder of QoL.


4.3 Results

4.3.1 Participants

A total of 1098 people (51% female, mean age 63.0 years) completed baseline

questionnaires. Of the 993 participants with complete MRI data at Phase 1 and

were therefore invited to return for Phase 2, 875 completed Phase 2 and 768

completed Phase 3. Participants who failed to complete Phase 2 or 3 (including

those who did not have baseline MR imaging), were older, had higher BMI and

pain at more sites at baseline than those who remained in the study.

4.3.2 Characteristics of the study population at baseline

Table 1 displays the characteristics of the cohort at baseline, stratified by

median AQoL score. Those with poorer QoL were older, had higher BMI,

walked fewer steps per day, were more likely to be retired or receiving a

disability pension and less likely to be employed; and more likely to have no

formal educational qualifications (Table 1).


Table 4.1: Characteristics of the study population at baseline, by quality of life†

QoL better than median Mean ± SEM n (%) n= 525

QoL at median or worse Mean ± SEM n (%) n= 573

p–value

Age (years) 61.9 ± 0.3 64 ± 0.3 <0.001

Gender (% male) 51 47 0.176

BMI weight (cm) / (height (m))2 27.3 ± 0.2 28.4 ± 0.2 <0.001

Height (cm) 167.7 ± 0.4 166.3 ± 0.4 0.006

Weight (kg) 77 ± 0.6 78.7 ±0.6 0.060

Current smokers (%) 12 12 0.782

Number of steps per day 10373.9 ± 158.3 8597.9 ±154.7 <0.001

Education Level <0.001

No formal qualification 54 (10) 126 (22)

School or Intermediate certificate

104 (20) 114 (20)

Higher School or Leaving Certificate

114 (22) 107 (19)

Trade / apprenticeship 59 (11) 78 (14)

Certificate / diploma 122 (23) 95 (17)

University degree or higher 72 (14) 52 (9)

Current employment

Employed / self–employed (full or part time)

264 (50) 168 (29) <0.001

Retired 178 (34) 240 (42)

Disability pension 4 (0.8) 69 (12)

Doctor–diagnosed rheumatoid arthritis (%)

6 18 <0.001

Leg strength (kg) 101.6 ± 1.38 86.3 ± 1.4 <0.001

† QoL was not normal and hence dichotomized at the median.

They also had higher prevalence of diagnosed osteoarthritis (OA) and pain at all

sites (Table 4.3).


Health–related QoL scores at baseline were skewed with a mean AQoL score

of 7.4 (SD 4.9) and a median of 7.0 (range 0 to 29). Summary results for

individual subscales are shown in Error! Reference source not found..

Table 4.2: Assessment of Quality of Life (AQoL)† subscales at baseline: mean scores and range

Mean (sd) n=1098

Median

Range

Illness 3.2 (2.6) 3 0 – 9

Independent Living 0.3 (0.9) 0 0 – 7

Relationships 0.7 (1.0) 0 0 – 8

Physical senses 0.9 (1.0) 1 0 – 5

Psychological wellbeing 2.3 (1.6) 2 0 – 9

Total AQoL score 7.4 (4.9) 7 0 – 29

†Higher scores indicate poorer QoL Distribution was skewed and kurtotic, hence analyses are transformed using a square root transformation, with back transformed results presented


Table 4.3: Osteoarthritis correlates of total AQoL score at baseline, using linear regression

Prevalence %

Step 1: Multivariable β

(95% CI)

Adjusted for age, sex and BMIf

Step 2: Multivariable β

(95% CI)§

Further adjusted for all variables significant in

Step 1

Diagnosed OA of:

Neck 168 (15) 2.72 (1.80 to 3.64) -0.32 (-0.96 to 0.32)

Shoulders 193 (18) 3.58 (2.34 to 4.81) 0.23 (-0.64 to 1.10)

Back 167 (15) 3.41 (2.54 to 4.28) 0.71 (0.02 to 1.41)

Hips 97 (9) 3.05 (1.93 to 4.17) 0.04 (-0.74 to 0.82)

Hands 113 (10) 2.32 (1.41 to 3.23) 0.09 (-0.55 to 0.72)

Knees 152 (14) 2.48 (1.52 to 3.43) 0.15 (-0.55 to 0.85)

Feet 103 (9) 3.40 (2.21 to 4.59) 0.30 (-0.49 to 1.09)

Hip JSN (yes / no) 377 (37) 0.34 (-0.31 to 0.99) –

Knee JSN (yes / no) 688 (67) 0.06 (-0.60 to 0.72) –

Hip osteophyte (yes / no)

190 (19) -0.10 (-0.89 to 0.69) –

Knee osteophyte (yes / no)

143 (14) -0.31 (-1.21 to 0.59) –

Pain in the:

Neck (yes / no) 514 (47) 3.14 (2.58 to 3.71) 0.65 (0.16 to 1.15)

Shoulder (yes / no) 674 (62) 3.35 (2.77 to 3.93) 1.03 (0.52 to 1.54)

Back (yes / no) 481 (44) 2.94 (2.39 to 3.50) 0.58 (0.12 to 1.05)

Hip (yes / no) 481 (44) 2.44 (1.83 to 3.04) 0.26 (-0.18 to 0.70)

Hand (yes / no) 505 (46) 2.63 (2.05 to 3.22) 0.50 (0.04 to 0.96)

Knee (yes/no) 451 (41) 2.72 (2.13 to 3.31) 0.41 (-0.04 to 0.86)

Foot (yes / no) 412 (38) 3.27 (2.64 to 3.89) 1.13 (0.62 to 1.63)

Statistically significant (p≤0.05) results indicated in bold type f after adjustment for age, sex and BMI § further adjusted for diagnosis of RA, arthritis at all sites or pain at all sites and leg strength § R2 for final model (Step 2)=27%; R2 excluding pain is 13%; R2 pain alone=23%.

Diagnosis of RA and leg strength were also associated with QoL, as expected,

(Table 4.1), and were adjusted for in final models. Pain at the anatomical

regions of interest was common (prevalence 38–62%), with 87% of participants

reporting pain in at least one joint. 8% of patients reported pain in all seven

regions.


4.3.3 Correlates of quality of life at baseline: cross–sectional analysis

Since presence of pain at the various sites was not strongly collinear,

(Pearson’s correlation r= 0.21 – 0.51), individual sites were entered into the

model separately.

Table 4.3 shows that physician diagnosis of OA at any of the sites was

associated with poorer QoL after adjustment for age sex and BMI, but only

physician diagnosed OA of the back remained significant after further

adjustment for RA, diagnosed OA at other sites and pain. Radiographic OA of

the hip or knee (JSN, osteophytes) were not associated with QoL in any

analysis. Presence or absence of pain at five of the seven sites were

independently associated with poor QoL after further adjustment for diagnosis

of RA, leg strength, diagnosed OA and pain at other sites. Knee pain was of

borderline statistical significance after adjustment for all correlates, p=0.076),

and hip pain was not significant.

The proportion of variance explained by the final model (R2, n=1017) was 27%,

of which 23% was explained by pain. There was also a strong linear

association between the number of sites at which participants reported pain and

QoL (Figure 4.1), suggesting a dose–response relationship. This association

was significant at all three time points, and relatively constant over time

(interaction p=0.602).


Figure 4.1: Mean total Assessment of Quality of Life (AQoL) score over time, by number of sites at which participants report pain and using multilevel mixed–effects linear regression

We conducted sensitivity analyses without the psychological wellbeing subscale

in order to assess whether the results from our total AQoL score were still valid

after removing questions related to psychological factors. The same variables

remained significant and coefficients were similar.


4.3.4 Correlates of quality of life over time: Longitudinal analysis

Mean AQoL scores were 7.36 (95% CI 7.07 – 7.65) at Phase 1, 7.53 (95% CI

7.20 – 7.87) at Phase 2 and 7.82 (95% CI 7.47 – 8.17) by Phase 3. Average

AQoL scores had significantly worsened by Phase 3 (p=0.047), but not Phase 2

(0.44) using unadjusted data and unpaired t–tests. After adjusting for the

changing composition of the sample over time using linear mixed models,

reduction in means was significant at both Phase 2 and 3 (p<0.001).

Table 4.4 shows a similar pattern of correlates of QoL to the analysis of

correlates at baseline, although most effect sizes were smaller.

After 2.6 years of observation, diagnosed OA (all sites) and presence or

absence of pain (all sites) were significant. After further adjustment for the

factors outlined above, diagnosed OA at the back remained significant as did

pain at six of the seven anatomical sites. There were no significant interaction

terms after adjustment for confounders and other covariates.

After five years of observation, pain at all sites was a significant independent

determinant of QoL (Table 4.4). QoL amongst participants with neck pain

remained stable whilst steadily worsening in those with no neck pain (p=0.02 for

interaction) but all other tests for interaction were not significant.

Table 4.4: Longitudinal analysis of arthritis correlates of total AQoL score over five years of follow up, using multilevel mixed–effects modelling

Baseline to Phase 2 (2.6 year follow up)

Baseline to Phase 3 (5 year follow up)

Step 1:

Multivariable (adj. age sex BMI, change in BMI and

age over time)

Step 2:

Multivariable Adjusted further¥

Step 1:

Multivariable (adj. age sex BMI, change in BMI and

age over time)

Step 2:

Multivariable

Adjusted further

Diagnosed OA of: Neck 1.55 (0.96 to 2.15) 0.01 (-0.5 to 0.52)

Shoulders 1.92 (1.22 to 2.61) 0.37 (-0.23 to 0.96)

Back 1.76 (1.23 to 2.28) 0.59 (0.12 to 1.06)

Hips 1.19 (0.54 to 1.84) -0.20 (-0.73 to 0.32)

Hands 1.35 (0.79 to 1.90) 0.19 (-0.28 to 0.66)

Knees 1.50 (0.91 to 2.08) 0.15 (-0.34 to 0.64)

Feet 1.40 (0.72 to 2.09) 0.12 (-0.44 to 0.68)

Presence or absence of pain in the:

Neck 1.79 (1.4 to 2.18) 0.55 (0.19 to 0.91) 1.20 (0.89 to 1.51) 0.42 (0.14 to 0.71)

Shoulders 1.80 (1.42 to 2.18) 0.66 (0.31 to 1.00) 1.36 (1.06 to 1.66) 0.64 (0.36 to 0.91)

Back 1.82 (1.45 to 2.19) 0.67 (0.33 to 1.00) 1.39 (1.09 to 1.68) 0.66 (0.39 to 0.94)

Hips 1.46 (1.07 to 1.85) 0.52 (0.19 to 0.85) 1.16 (0.85 to 1.47) 0.47 (0.20 to 0.74)

Hands 1.20 (0.82 to 1.59) 0.19 (-0.13 to 0.51) 0.91 (0.60 to 1.22) 0.27 (0.01 to 0.53)

Knees 1.51 (1.12 to 1.90) 0.43 (0.10 to 0.75) 1.10 (0.79 to 1.41) 0.44 (0.17 to 0.70)

Feet 0.98 (0.65 to 1.32) 0.36 (0.09 to 0.62) 0.75 (0.47 to 1.02) 0.26 (0.03 to 0.49)

Statistically significant (p≤0.05) results indicated in bold type ¥ Results further adjusted for diagnosed OA at all sites, pain at all sites, presence of rheumatoid arthritis and leg strength Results further adjusted as for the analyses for Baseline to Phase 2, but without Diagnosed OA as this was not asked at Phase 3. 5 year follow up data includes data collected at Phase 1, 2 and 3 and is not limited to participants with complete data. Radiographs not included as they were only collected at Phase 1.


4.4 Discussion

This population–based prospective study describes the contribution of

multiple osteoarthritic correlates of QoL over five years of observation.

Physician diagnosed OA of the back and pain at all sites were independent

and stable correlates of QoL, and pain at multiple sites has an additive

deleterious effect on QoL. With the exception of the back, pain appeared to

mediate the association between diagnosed OA and QoL. Radiographic

osteoarthritis was not associated with QoL.

In this study, the strongest musculoskeletal correlate of QoL was pain. Pain

is a priority for patients seeking care (Heiberg and Kvien, 2002) and thus it is

perhaps not surprising that pain largely mediated the association between

doctor diagnosed OA and QoL. Further, pain assessed at one site in cross

sectional studies is known to be associated with poorer QoL (Hill, 2008;

Rezai, 2009), but no studies that have looked at pain at many sites. Our data

suggests that pain at all sites measured independently contribute to QoL,

there is a dose response association between number of pain sites and QoL,

and severity of pain is also related to QoL. Our data suggests that pain is

very common in older adults in the community. Given that pain at individual

joints and overall number of sites of joint pain were associated with poor

QoL, this suggests that interventions to reduce the frequency and intensity of

pain may be effective in improving QoL at the population level.

While there are some inconsistencies in the three analyses, the most weight

should be put on the analysis over five years as it uses all the data and

therefore is the most powerful. These results confirm and extend the findings

of Woo et al (2009), where pain at the back, hip (men only) and knees was


associated with QoL over time in ethnic Chinese. Pain in the shoulders and

back were the most important factors in our analyses, but knees, hips and

even hands and feet were significant. The inconsistency with the hip may, in

part, be due to patients have difficulty locating the correct anatomical position

of the hips (Birrell, 2005), or that pain in the knee can actually be referred

from the hip (Zhai, 2006). Knee pain was of borderline significance in cross–

sectional analyses but became significant over time.

Diagnosed OA of the back was also an independent correlate of poor QoL

(both in cross–sectional and longitudinal analyses), but diagnosed OA of the

neck, shoulders, hips, hands, knees and feet were not once adjustment was

made for the multiple sites of OA and for pain. This suggests that while pain

mediates the associations between diagnosed OA and QoL at sites other

than the back (neck, shoulders, hands, hips, knees and feet), the association

between diagnosed OA of the back and QoL is only partially mediated by

pain. It is well known that psychological factors such as depression are

associated with chronic back pain but unfortunately we were not able to

assess these in the current study.

There was no association between radiographic osteoarthritis and QoL at

baseline, after adjusting for age, sex and BMI. This suggests that

radiographic findings make no independent contribution to QoL, consistent

with other studies which showed that the association between radiographic

OA of the hand and function was largely mediated by pain (Jones, 2001), and

that pain is a better predictor of disability than radiographic change (Creamer,

2000; Guccione, 1990; Jordan, 1997). This differs from the findings of other

studies (Norimatsu, 2011; Muraki, 2011), who found that radiographic OA

was associated cross–sectionally with different disease–specific measure of


QoL, after adjustment for pain and other covariates. Both of these measures

of QoL had pain as a subscale, so this may explain why they found an

association yet we did not. A strength of our study is that, unlike Norimatsu

and colleagues, we have collected (self–reported) diagnosis of OA and

radiographic findings separately (in addition to pain), and while finding them

to be correlated, when both diagnosis and radiography appear together in

one model, radiographic findings are no longer associated with QoL. Our

data demonstrates that diagnosis of OA reflects more than radiographic

evidence of joint damage, but that with the exception of diagnosed OA of the

back, is not independent of pain.

Strengths of this study include the random population–based sampling and

comprehensive data collection, and five–year period of observation, providing

excellent external validity for our findings. Limitations include absence of

information on psychological factors, such as diagnosed mental health

conditions or psychological distress: this limits our ability to consider such

conditions as covariates or effect modifiers, but our model is robust whether

or not the mental health component of QoL is included, suggesting this is not

a major issue. Additionally, the initial response rate of 57%, while lower than

desirable, is similar to other comparable Australian studies (Hill, 2008), and a

lower response rate does not mean that relationships between outcome and

exposure are necessarily biased (Carter, 2012). Participants who did not

continue in the study were older, heavier, with pain at more sites at baseline

than the remaining participants. This should reduce the observed effect size

of our findings, but since few associations were of borderline significance this

should not have altered our conclusions. We did not seek to confirm doctor–

diagnosed cases of arthritis, and therefore participants may have under–or


over–reported diagnosed arthritis, and the extent to which this may have

affected the findings of the study is unclear. However, use of self–reported

doctor diagnosed OA appears to be a reasonable proxy for OA, as JSN was

more common in participants reporting doctor–diagnosed OA at the hips and

knees (hips OR 2.3, p<0.001; knees OR 1.6, p=0.023), and osteophytes

more common in participants reporting knee (OR 4.10, p<0.001), but not hip

OA (OR 0.94, p=0.83). We had X–rays only of the hips and knees, and so

are not able to assess the association between ROA and QoL at other

anatomic sites. However, unless the causal pathways at other sites are

substantially different to those at the knees and hips, it is unlikely that

radiographic OA at these sites would add any new information to the models.

In conclusion, pain is the strongest musculoskeletal correlate of QoL, which

has an additive deleterious effect on QoL, and mediates the effect of

diagnosed OA (except in OA of the back). These associations are stable

over time suggesting that pain has a consistent rather than an increasing

deleterious effect. Since we found that the same factors were associated

with quality of life over time as in the baseline analysis, this suggests that

quality of life tracks over a five year period.

This chapter has been removed for

copyright or proprietary reasons.

Chapter 5

Moderate vitamin D deficiency is associated with changes in knee and hip pain in older adults: a 5-year longitudinal study.

Published in:

http://www.ncbi.nlm.nih.gov/pubmed/23595144

Laslett LL, Quinn SJ, Burgess JR, Parameswaran V, Winzenberg TM, Jones G, Ding C. .2013, Moderate vitamin D deficiency is associated

with changes in knee and hip pain in older adults: a five year longitudinal study. Ann Rheum Dis. 2013 [epub before print].


Chapter 6

Treatment with 4Jointz reduces knee pain over 12 weeks of treatment in patients with clinical knee osteoarthritis: a randomised controlled trial.

Published In:


doi: 10.1016/j.joca.2012.07.019

Laslett LL, Quinn S, Darian-Smith E, Kwok M, Fedorova T, Körner H, Steels E, March L, Jones G. 2012, Treatment with 4Jointz reduces knee pain over 12 weeks of treatment in patients with clinical knee osteoarthritis: a randomised

controlled trial. Osteoarthritis Cartilage. 2012;20(11):1209-16.


Chapter 7

Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial.

Published In:


doi: 10.1136/annrheumdis-2011-200970.

Laslett LL, Doré DA, Quinn SJ, Boon P, Ryan E, Winzenberg TM, Jones G. 2012, Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a

randomised controlled trial. Ann Rheum Dis. 2012 Feb 21;71(8):1322-8.


Chapter 8: Summary and future directions

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Page 182


Page 183

Chapter 8. Summary and future directions

8.1 Introduction

As has been described in this thesis, arthritis is the most common cause of

chronic pain in older people (Peat, 2001; Britt, 2010), affecting an estimated

31% of Australians (AIHW, 2010), and is expensive, constituting the fourth

largest component of direct health expenditure in 2004–05, at AUD$4.0

billion (AIHW, 2009). Increases in expenditure are predicted to continue, and

to increase by a factor of 2 by 2032–33 (Goss, 2008), driven by the ageing

population the volume of treatment(s) for each person. Pain is an important

clinical symptom, predicting clinically relevant outcomes including

disability (Croft, 2005) and joint replacement (Gossec, 2005; Hawker, 2006;

Conaghan, 2010; Jüni, 2003), and is a priority for patients (Heiberg and

Kvien, 2002).

Despite the large disease burden, there are no proven preventative

strategies, but there have been a few clinical trials in addition to the work

presented in this thesis (Bruyere, 2008; Esenyel, 2012; Reginster, 2012), all

using agents with well–described effects in bone. None have demonstrated

change in structural endpoints in addition to pain. Conventional treatment of

OA remains mostly palliative and expensive and there is considerable scope

for improvements in treatments, both in terms of treatments which modify

structure and pain, and safe treatments which confer additional pain benefits.

8.2 Future directions

8.2.1 Musculoskeletal pain and quality of life

Investigations on the impact of musculoskeletal pain and radiographic OA on

health related QoL in older adults living in the community are presented in

Chapter 4. We concluded that radiographic findings (JSN, osteophytes)


Page 184

make no independent contribution to QoL, and that pain tracks over time.

This supports a focus on pain–relieving interventions, and that reducing pain

could change the trajectory of quality of life in the medium term. Agents that

slow structural progression of osteoarthritis are extremely important, but such

agents must also improve pain if they are to improve the quality of people’s

lives.

8.2.2 Serum 25–OHD and change in knee and hip pain over time

Investigations on associations between serum 25–OHD and change in knee

pain over 5 years and change in hip pain over 2.6 years are presented in

Chapter 5. We found that there was no linear association between serum

25–OHD and change in knee or hip pain using the original values of 25–

OHD, but that having serum 25–OHD below 25 nmol/L (moderately deficient)

was a novel determinant of musculoskeletal pain. Mild vitamin D deficiency

is endemic in Tasmanian adults (van der Mei, 2012), as it is elsewhere in the

world but moderate deficiency is uncommon in most populations This study

suggests that supplementation may help pain in this small subgroup but this

needs to be tested in randomised trials before supplementation can be

recommended, or guidelines developed for the use of supplements. A

randomised controlled trial of the effects of vitamin D in OA is underway at

our centre (the Vitamin D Effects on OA, or VIDEO study (Cao, 2012)), in

which vitamin D supplementation (50,000 IU compounded vitamin D3

capsule monthly) or identical inert placebo is issued monthly to participants

with symptomatic knee OA and serum 25–OHD of 12.5 – 60 nmol/L for two

years. Outcomes from the VIDEO study will include the effect of vitamin D3

supplementation on pain, as measured by the WOMAC pain score.

Therefore, the VIDEO study will be able to determine whether vitamin D


Page 185

supplementation is effective in improving knee pain in persons with clinical

knee osteoarthritis, and whether this effect is observed only in persons with

baseline 25–OHD levels of 25–30 nmol/L or whether such benefits apply to

all study patients (12.5 to 60 nmol/L).

Two recent trials have demonstrated increased risk of fractures (Sanders,

2010; Smith, 2007) and falls (Sanders, 2010) using large (300,000IU) annual

intramuscular doses of vitamin D2 or vitamin D3. This has overturned the

previous view attained from studies with more frequent dosing regimes that

vitamin D supplementation was safe as long as 25–OHD levels remained

below the toxic levels of 275–500 nmol/L (Jones, 2008). The results of these

trials are a cautionary tale of the importance of randomised trials in

determining efficacy and safety before treatments are introduced into clinical

practise.

8.2.3 4Jointz trial

A randomised controlled trial of 4Jointz vs placebo was conducted (see

Chapter 6). We demonstrated that topical treatment using 4Jointz is a safe

and effective treatment for the symptoms of knee OA in participants with

clinical OA and moderate knee pain on most days. In particular, use of

4Jointz reduced pain and increased muscle strength, but had no effect on

systemic inflammation or cartilage breakdown over 12 weeks of treatment.

This was particularly notable as these benefits were in addition to the effect

of other treatments.

We observed higher dropout rates in the group receiving 4Jointz, partially

attributable to rashes (localised skin irritation at the site of application). This

highlights the importance of conducting clinical trials on all medications, as

rashes were not reported as an adverse event in previous studies using


Page 186

topical preparations of comfrey. It is possible that rashes were related to the

other components of 4Jointz, such as tannic acid. The pharmaceutical

company may consider how they can make the preparations less irritating in

order to minimise rashes.

Since post-hoc analyses suggested that treatment may be most effective in

women and those with milder radiographic OA, future studies should

consider including these populations, and for longer duration than 12 weeks.

This trial also suggests the value of using add–on trials in OA, where a

medication is given to patients in addition to their other medications.

8.2.4 ZAP trial

This trial Investigated the effect of a single dose of zoledronic acid (5mg) on

persons with moderately severe knee pain, clinical knee OA and BMLs (see

Chapter 7). Use of ZA significantly reduced VAS pain scores, areal size of

BMLs after 6 months, and proportion with improvement in BML size. This is

the first occasion that any osteoarthritic treatment has demonstrated

structural modification of BMLs (or indeed any other structure); therefore this

observation is completely novel. Previous investigations of potential

structure–modifying drugs did not live up to expectations (Bingham, 2006;

Raynauld, 2008). For ZA to be truly disease modifying, evidence of change

in cartilage endpoints or joint replacement will be required. To this end, our

research group have been successful in obtaining a National Health and

Medical Research Council Project Grant (2012 Application ID 1045415).

This will fund a two year randomised controlled trial of yearly infusion of ZA

(5mg) on cartilage volume, along with other endpoints collected in the shorter

trial presented as part of this thesis (BMLs, pain, function) as well as cartilage

markers and joint replacement.


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One of the observations from the ZAP trial was that 39% of participants

receiving ZA improved, whereas only 18% receiving placebo improved,

representing an odds ratio of 5.0 (p=0.044). This is a significant difference,

showing that ZA is effective in reducing the size of BMLs, with large enough

reductions that we expected to observe a clinically significant reduction in

pain. However, even in the group who received ZA, 61% had an increase in

their BMLs or no change (compared to 82% in the placebo group). Clearly

some patients are responding to treatment whereas others are not. Since

the pathology of BMLs are heterogeneous (Zanetti, 2000; Taljanovic, 2008),

one of the explanations for this is that some histological profiles respond to

osteoclast–mediated ZA therapy whereas others do not. Unfortunately, no

markers are yet available for typing of BMLs using non-invasive methods, as

biopsies are not feasible in this population. Similarly, some participants had

evidence of reduction in the size of BMLs but not reduction in pain, which we

attribute to presence of other pathologies which cause pain, such as joint

effusions. In the new, NHMRC–funded two–year RCT with cartilage

endpoints which will begin in 2013, we plan to investigate the effect of other

pathology and disease characteristics on response to ZA.

This clinical trial also provides evidence of a “bone-specific” phenotype of

OA (Walsh and Chapman, 2011) which is highly likely to be responsive to

treatment with bisphosphonates.

8.2.5 Challenges in clinical trials in osteoarthritis

8.2.5.1 Choice of study patients

Animal models suggest that synovitis and BMLs are very early signs of OA,

preceding cartilage erosion and degeneration (Libicher, 2005); thus these

may be optimal markers to target in achieving disease modification, as they


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occur early in the disease course when less damage has occurred. Yet

typical patients in knee OA trials with structural endpoints are patients with

much later stages of OA, ie Kellgren and Lawrence grade 2 and 3.

Intervening earlier in the disease course is always preferable, but additionally

choosing patients with radiographic OA for interventional studies has

additional problems, as the presence of radiographic OA predicts patients

who lose cartilage faster (Mazzuca, 2005; Saunders, 2011), and this has

implications for participant selection in clinical trials as the outcomes of

treating these different Oa phenotypes may have different outcomes. This

suggests that selection of study patients is crucial when planning intervention

studies, and in evaluating their results.

8.2.5.2 Choice of outcome measures

Change in joint space width (JSW) at the tibiofemoral joint is currently the

gold standard for assessing osteoarthritis disease modification in clinical

trials, (Conaghan, 2011) and is mandated by the Food and Drug

Administration and European Medications Agency as a proxy endpoint to

determine efficacy of disease modifying osteoarthritis drugs. In cross-

sectional studies, the amount of cartilage volume assessed by magnetic

resonance imaging (MRI) and JSW as assessed by radiograph are strongly

correlated. However, JSW is also associated with meniscal

pathology (Berthiaume, 2005; Adams, 1999) and cartilage defects, (Ding,

2005) suggesting that multiple abnormalities contribute to narrowing of joint

space width (JSW). There is limited longitudinal data; however data from our

centre demonstrates that both change in cartilage volume and meniscal

extrusions modestly predict change in joint space width; however, over 90%

of the variation in change in joint space remains unexplained (Hall, 2012).


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Using MR imaging in preference to radiographs should be a better outcome

measure as it enables direct (vs indirect) visualisation of these structures,

and has been validated in cadaveric studies, (Cicuttini, 1999) and predicts

clinical outcomes such as joint replacement (Cicuttini, 2004). Overall,

cartilage loss seen on MRI is more sensitive than X-ray change as an

outcome measure.

There are other issues in using radiographs as outcomes. Structures seen

on radiographs may not be direct sources of pain, and therefore are of limited

value in assessing factors causing pain. Also, the changes in JSW in some

trials (even large trials) have shown mean changes that were less than the

measurement error of the technique of evaluation}, despite large numbers of

patients and state of the art protocols. (Brandt, 2005; Bingham, 2006)

Despite these shortcomings, MR imaging is yet to replace radiographs as

routine an outcome measures in studies investigating structural outcomes.

8.2.5.3 Subtypes or phenotypes of osteoarthritis

Osteoarthritis can result from an extremely diverse range of pathologies and

pathological processes, resulting in a heterogeneous mix of pathological

processes and tissue subtypes amongst patients diagnosed with OA. This

creates a challenge for clinical trials in that a treatment applied to a particular

study group may only be effective in a small subset of that group. Therefore,

separating study populations into subgroups with particular features that are

likely to respond (or not respond) to particular treatments have

advantages (Lane, 1999). One such phenotype is a “bone–specific

phenotype” (Walsh and Chapman, 2011) in patients with BMLs. Bone

marrow lesions identify regions of increased subchondral bone turnover and

therefore may provide a biomarker that can predict response to


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bisphosphonates. Phenotypes postulated by other authors are post-

traumatic (acute or repetitive), metabolic, ageing, genetic and pain (Bijlsma,

2011), and rate of progression or prognosis (Lane, 1999); each with different

aetiological features, causal pathways, affected sites and effective

treatments. Identifying subtypes or phenotypes of OA is likely to assist in

targeting treatment to patients who are the most likely to benefit.

8.2.6 Conclusions

In conclusion, this analysis of data from a prospective population–based

cohort study and two randomised controlled trials demonstrate that pain is an

independent correlate of quality of life, that one of the determinants of knee

(and possibly hip) pain over time is moderate vitamin D deficiency, and that

treatment of patients with clinical knee OA and pain on most days with either

ZA infusion or application of 4Jointz reduces knee pain. Most importantly, we

have demonstrated that ZA may be a disease–modifying OA drug which

reduces the size of BMLs in addition to reducing pain. Future work is

underway on larger multicentre clinical trials.

Appendix1: Questionnaires

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Appendix 1: Questionnaires

Appendix1: Questionnaires

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Appendix 1: WOMAC questionnaire; questions on diagnosed OA and joint pain

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Appendix 1 Questionnaires

A1.1 The Western Ontario and McMaster Universities

Osteoarthritis Index (WOMAC), and questions on diagnosed

OA and joint pain

WOMAC pain questionnaire; questions on diagnosed OA and joint pain

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Appendix 1: WOMAC questionnaire; questions on diagnosed OA and joint pain

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Appendix 1: TASOAC smoking questions

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A1.2 Smoking questions


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Appendix 1: AQoL questionnaire

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A1.3 Assessment of quality of life (AQoL)

ID______

Assessment of Quality of Life (AQOL)

INSTRUCTIONS: Please circle the alternative that best describes you during the last week.

ILLNESS

1.Concerning my use of prescribed medicines: A.I do not or rarely use any medicines at all. B.I use one or two medicinal drugs regularly. C.I need to use three or four medicinal drugs regularly. D.I use five or more medicinal drugs regularly. 2.To what extent do I rely on medicines or a medical aid? (NOT glasses or a hearing aid.) (For example: walking frame, wheelchair, prosthesis etc.) A.I do not use any medicines and/or medical aids. B.I occasionally use medicines and/or medical aids. C.I regularly use medicines and/or medical aids. D.I have to constantly take medicines or use a medical aid. 3.Do I need regular medical treatment from a doctor or other health professional? A.I do not need regular medical treatment. B.Although I have some regular medical treatment, I am not dependent on this. C.I am dependent on having regular medical treatment. D.My life is dependent upon regular medical treatment.


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INDEPENDENT LIVING 4.Do I need any help looking after myself? A.I need no help at all B.Occasionally I need some help with personal care tasks. C.I need help with the more difficult personal care tasks. D.I need daily help with most or all personal care tasks. 5.When doing household tasks: (For example, preparing food, gardening, using the video recorder, radio, telephone or washing the car) A.I need no help at all. B.Occasionally I need some help with household tasks. C.I need help with the more difficult household tasks. D.I need daily help with most or all household tasks. 6.Thinking about how easily I can get around my home and community: A.I get around my home and community by myself without any difficulty. B.I find it difficult to get around my home and community by myself. C.I cannot get around the community by myself, but I can get around my home with some difficulty. D.I cannot get around either the community or my home by myself.

SOCIAL RELATIONSHIPS 7.Because of my health, my relationships (for example: with my friends, partner or parents) generally: A.Are very close and warm. B.Are sometimes close and warm. C.Are seldom close and warm. D.I have no close and warm relationships. 8.Thinking about my relationship with other people: A.I have plenty of friends, and am never lonely. B.Although I have friends, I am occasionally lonely. C.I have some friends, but am often lonely for company. D.I am socially isolated and feel lonely.


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9.Thinking about my health and my relationship with my family: A.My role in the family is unaffected by my health. B.There are some parts of my family role I cannot carry out. C.There are many parts of my family role I cannot carry out. D.I cannot carry out any part of my family role.

PHYSICAL SENSES 10.Thinking about my vision, including when using my glasses or contact lenses if needed: A.I see normally. B.I have some difficulty focusing on things, or I do not see them sharply. For example: small print, a newspaper, or seeing objects in the distance. C.I have a lot of difficulty seeing things. My vision is blurred. For example: I can see just enough to get by with. D.I only see general shapes, or am blind. For example: I need a guide to move around. 11.Thinking about my hearing, including using my hearing aid if needed: A.I hear normally. B.I have some difficulty hearing or I do not hear clearly. For example: I ask people to speak up, or turn up the TV or radio volume. C.I have difficulty hearing things clearly. For example: Often I do not understand what is said. I usually do not take part in conversations because I cannot hear what is said. D.I hear very little indeed. For example: I cannot fully understand loud voices speaking directly to me. 12.When I communicate with others: (For example: by talking, listening, writing or signing) A.I have no trouble speaking to them or understanding what they are saying. B.I have some difficulty being understood by people who do not know me. I have no trouble understanding what others are saying to me. C.I am only understood by people who know me well. I have great trouble understanding what others are saying to me. D.I cannot adequately communicate with others.


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PSYCHOLOGICAL WELLBEING 13.If I think about how I sleep: A.I am able to sleep without difficulty most of the time. B.My sleep is interrupted some of the time, but I am usually able to go back to sleep without difficulty. C.My sleep is interrupted most nights, but I am usually able to go back to sleep without difficulty. D.I sleep in short bursts only. I am awake most of the night. 14.Thinking about how I generally feel: A.I do not feel anxious, worried or depressed. B.I am slightly anxious, worried or depressed. C.I feel moderately anxious, worried or depressed. D.I am extremely anxious, worried or depressed. 15.How much pain or discomfort do I experience? A.None at all. B.I have moderate pain. C.I suffer from severe pain. D.I suffer unbearable pain. Hawthorne & Richardson (1996) All rights reserved. Assessment of Quality of Life (AQoL) instrument. Melbourne, Centre for Health Program Evaluation. The AQoL may not be copied or used without permission.

Appendix 1: Knee Injury and Osteoarthritis Scale

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A1.4 Knee Injury and Osteoarthritis Scale


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This Appendix has been removed for

copyright or proprietary reasons

Appendix 2

Excess body fat is associated with higher risk of vertebral deformities in older women but not in men: a cross-sectional study.

Published In:


Laslett LL, Just (nee Foley) SJ, Quinn SJ, Winzenberg TM, Jones G. 2012, Excess body fat is associated with higher risk of vertebral deformities in older women

but not in men: a cross-sectional study. Osteoporos Int. 2012;23:67-74.


Appendix 3: 4Jointz report

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Appendix 3: Report on 4Jointz trial prepared for the pharmaceutical company


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Appendix 3 A 12 week randomised controlled trial

of 4Jointz for symptomatic knee osteoarthritis

Report prepared for Arthritis Relief Plus Ltd

February 2012


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Report authors

1Laura L Laslett, 2Stephen J Quinn, 1Erica Darian-Smith, 1Michael Kwok,

3Tanya Fedorova, 4Elizabeth Steels, 3Lyn March 1Graeme Jones

1Menzies Research Institute Tasmania, University of Tasmania.

2 Clinical Effectiveness Cluster, Flinders University

3Royal North Shore Hospital, University of Sydney.

4ASN Research.

Address correspondence to: Prof Graeme Jones, Menzies Research Institute

Tasmania, University of Tasmania, Private Bag 23, Hobart, Tasmania 7000,

Australia, phone +61 3 6226 7705, fax +61 3 6226 7704 E-mail:

[email protected]

mailto:[email protected]


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List of abbreviations ACR American College of Rheumatology

BMI Body Mass Index

CTX-2 C-terminal cross linking telopeptide of type II collagen: a marker of

cartilage tissue degradation.

eGFR Estimated glomerular filtration rate: a measure of kidney function.

ITT Intent to treat: an approach to data analysis.

JSN Joint space narrowing: the space between tibia and femur, as seen

on radiographs.

KOOS Knee Injury and Osteoarthritis Outcome Score

IL-6 Interleukin-6, a marker of inflammation

OA Osteoarthritis

OARSI Osteoarthritis Research Society International

VAS Visual analog score: a tool for measuring pain intensity.


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Table of contents

A3.1 Introduction .................................................................................... 242

A3.2 Methods ..................................................................................... 245

A3.2.1 Trial design .......................................................................... 245

A3.2.2 Settings and locations .......................................................... 245

A3.2.1.1 Inclusion and exclusion criteria ........................................ 245

A3.2.3 Participants .......................................................................... 245

A3.2.4 Interventions ........................................................................ 246

A3.2.5 Outcomes ............................................................................ 247

A3.2.6 Outcome measures ............................................................. 247

A3.2.6.1 Pain and function ............................................................. 247

A3.2.6.2 Inflammation and cartilage breakdown ............................ 247

A3.2.6.3 OMERACT-OARSI response criteria ............................... 248

A3.2.6.4 Paracetamol usage ......................................................... 248

A3.2.6.5 Muscle strength ............................................................... 249

A3.2.6.6 Safety .............................................................................. 249

A3.2.7 Sample size ......................................................................... 249

A3.2.8 Randomisation and sequence generation ........................... 249

A3.2.9 Statistical methods ............................................................... 250

Results .................................................................................................... 251

A3.3.1 Study participants ................................................................ 251

A3.3.2 Outcomes ............................................................................ 254

Primary hypotheses ......................................................................... 254

Secondary outcomes ....................................................................... 254

A3.3.3 Individual outcomes ............................................................. 257

A3.3.3.1 Pain intensity (using visual analog scores) ...................... 257

A3.3.3.2 KOOS results .................................................................. 258

A3.3.3.3 Cartilage breakdown........................................................ 260

A3.3.3.4 Systemic inflammation ..................................................... 261

A3.3.3.5 Paracetamol use ............................................................. 262

A3.3.3.6 Leg strength .................................................................... 264

A3.3.3.7 OMERACT – OARSI response criteria ............................ 265

A3.3.4 Post-hoc analyses ............................................................... 266


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A3.3.4.1 Gender ............................................................................ 266

A3.3.4.2 OARSI grade and BMI ..................................................... 269

A3.3.5 Adverse events .................................................................... 271

Discussion ............................................................................................... 273

Conclusions ............................................................................................. 275

Reference List ......................................................................................... 311

LIST OF TABLES

Table A3.1: Baseline characteristics of study patients ............................... 253

Table A3.2: Effect of treatment with 4Jointz: study outcomes after four, eight and twelve weeks of treatment, using change models ................................ 255

Table A3.3: Offset effect- change in study outcomes when treatment ceases (between 12 and 16 weeks of observation) ................................................ 256

Table A3.4: Change in pain scores between baseline and twelve weeks, by gender and treatment group ....................................................................... 266

Table A3.5: Change in VAS score between baseline and twelve weeks, by OARSI grade and body mass index. ........................................................... 269

Table A3.6: Prevalence and number of adverse events, by treatment received ...................................................................................................... 272


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LIST OF FIGURES

Figure A3.1: Study flow chart ...................................................................... 252

Figure A3.2: Pain intensity (using the visual analog scores) over sixteen weeks of treatment, by treatment received ................................................. 257

Figure A3.3: Pain intensity (as measured using the KOOS questionnaire) over sixteen weeks of treatment, by treatment received ............................. 259

Figure A3.4: Symptom scale, as measured using the KOOS questionnaire, over sixteen weeks of treatment, by treatment received ............................. 259

Figure A3.5: CTX-2, by treatment received ................................................ 260

Figure A3.6: IL6, by treatment received ...................................................... 261

Figure A3.7: Proportion of participants using paracetamol over sixteen weeks of treatment, by treatment received ................................................. 262

Figure A3.8: Daily dose of paracetamol (mg) over sixteen weeks, in participants using paracetamol at baseline, by treatment received............. 263

Figure A3.9: Leg strength over sixteen weeks of treatment, by treatment received ...................................................................................................... 264

Figure A3.10: Response to treatment using a modified version of the OMERACT – OARSI response criteria, by treatment received ................... 265

Figure A3.11a and b: Effect of treatment on pain intensity in women and men, by treatment received ........................................................................ 267

Figure A3.12 a and b: Effect of treatment on KOOS pain score in women and men, by treatment received ........................................................................ 268

Figure A3.13a and b: Effect of treatment on pain intensity in persons by OARSI grade (0 and 1 vs 2), by treatment received ................................... 270


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Abstract

Objective: To assess the efficacy of thrice daily topical 4Jointz utilizing

Acteev technology (a novel and patented combination of a standardized

comfrey extract and a pharmaceutical grade tannic acid, 3.5 g/day), or

placebo on osteoarthritic knee pain, markers of inflammation and cartilage

breakdown over twelve weeks in a double-blind randomised controlled trial.

Patients and methods: Adults aged 50-80 years (n=133) with clinical knee

osteoarthritis (OA) according to the ACR criteria were randomised to receive

either 4Jointz or placebo in addition to existing medications. Pain and knee

function were measured using a visual analogue scale (VAS) and the Knee

Injury and Osteoarthritis Outcome Score (KOOS) scale at baseline, 4, 8 and

12 weeks. Inflammation was measured using IL-6 and cartilage breakdown

measured using CTX-2, at baseline and twelve weeks.

Results: Pain scores were significantly reduced in the group who received

4Jointz compared to the group who received placebo after twelve weeks

using both the VAS (-9.9mm, p=0.034) and the KOOS pain scale (5.7,

p=0.047). This effect decreased markedly within 4 weeks of cessation of

treatment. In addition, muscle strength improved compared to placebo (+2.9

kg, p=0.02) after twelve weeks. Changes in IL-6 and CTX-2 were not

significant (+0.1, p=0.98; -23.0, p=0.44). Reduction in paracetamol daily

dose in patients using paracetamol at baseline was clinically (but not

statistically) significant by twelve weeks (-404 mg, p=0.35). Post hoc

analyses suggested that the treatment may be most effective in women (VAS

-16.8mm, p=0.008) and those with milder radiographic osteoarthritis (VAS -

16.1mm, p=0.009). Local rash was more common amongst participants


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receiving 4Jointz (21% v 1.6%, IRR 13.2, p=0.013), but only 26% (n=4) of

participants with rashes discontinued treatment. There were no changes in

systemic blood results and no differences in adverse events between

patients receiving 4Jointz and placebo.

Conclusions: Topical treatment using 4Jointz reduced pain and increased

muscle strength but had no effect on inflammation or cartilage breakdown

over twelve weeks of treatment.


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A3.1 Introduction

Knee osteoarthritis (OA) is common and is associated with pain and ongoing

disability. Management of osteoarthritis involves symptom control, usually

non-steroidal anti-inflammatory medications (NSAIDs) or analgesic

medication in early arthritis, and then joint replacement when the disease

progresses to more severe stages.

The controversy surrounding the use of the COX-2 inhibitor class of NSAIDs

and heightened cardiovascular risk (Bombardier, 2000; Bresalier, 2005;

Caughey, 2011; Solomon, 2005), highlights the importance of finding safer

treatment options to minimise adverse side effects. Natural agents such as

capsaicin (Katz and Shah, 2009) and vitamins (McAlindon, 1996) have

demonstrated improved overall patient outcomes, and may play a role in

treatment of OA even if they are only moderately effective.

Comfrey (Symphytum officinale) is traditionally used for the treatment of bone

fractures, sprains and wounds (Bleakley, 2008), as it demonstrates anti-

inflammatory and analgesic properties. A topical comfrey application (vs.

placebo) on acute ankle sprains in 142 participants has been shown to

decrease pain and swelling and improve mobility (Koll, 2004). In other

studies on ankle distortions sole comfrey therapy was reported as being as

effective and possibly superior to diclofenac gel (D'Anchise, 2007; Predel,

2005). Comfrey has also been used in an earlier study to specifically treat OA

with two thirds of recipients reducing or discontinuing their NSAID

treatment (Koll and Klingenburg, 2002). Moreover, in a study involving 220

patients diagnosed with OA, those utilising topical Comfrey therapy reported

a marked reduction in VAS pain scores (Grube, 2007).


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Persons with OA have been reported to have high levels of free radicals and

reduced levels of antioxidants within the joint fluid (Regan, 2008). The

presence of oxygen free radicals in the synovial joint fluid of persons with

osteoarthritis act as chemical messengers responsible for the pathogenesis

of osteoarthritis (Yudoh, 2005). Antioxidants (such as tannic acid) are

protective against the extracellular matrix cartilage degradation that radicals

yield (Cho, 2009) and can also augment glycosaminoglycan binding to

collagen. This ultimately contributes to the structural reinforcement of

synovial articulating surfaces (Levanon and Stein, 1995). Preparations of

tannic acid have been found to be superior to placebo in reducing pain and

stiffness and improving physical function in primary OA (McAlindon, 1996).

Therefore, a number of complementary medicinal agents may be effective in

reducing pain and inflammation. A pilot study of treatment using two different

concentrations of comfrey vs placebo (Smith and Jacobson, 2011) showed

that the comfrey / tannic acid mixtures were both superior to placebo in

reducing WOMAC pain and stiffness scores. In a previous study, (Grube,

2007) researchers compared a comfrey root extract with placebo for painful

knee OA and observed a 40mm difference in pain VAS score, and 46mm

reduction in WOMAC score between comfrey and placebo after three weeks.

However, this trial has substantial methodological weaknesses which reduce

confidence in its’ findings. These include: short duration of follow up;

absence of baseline patient summary data; lack of information on how

participants were randomised, how blinding was achieved for patients or

assessors, or methods used to confirm knee OA.

This study compared the effect of thrice daily topical 4Jointz utilizing Acteev

technology (a novel and patented combination of a standardized comfrey


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extract and a pharmaceutical grade tannic acid, 3.5 g/day), or placebo on

osteoarthritic knee pain, muscle strength, and markers of inflammation and

cartilage breakdown over twelve weeks in participants aged >50 with

clinically diagnosed OA and a pain intensity score >40mm on a visual

analogue scale (VAS).


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A3.2 Methods

A3.2.1 Trial design

This study was a two centre double blind parallel-group placebo controlled

randomised trial of topical treatment 4Jointz vs placebo with a 1:1 allocation

ratio.

A3.2.2 Settings and locations

Participants were recruited from September 2010 to May 2011 through

advertising in local print media in Hobart, Tasmania and Sydney, New South

Wales in Australia. Participants attended clinics at either the Menzies

Research Institute Tasmania in Hobart, or the Royal North Shore Hospital in

Sydney.

A3.2.1.1 Inclusion and exclusion criteria

Participants were aged >50 years, with clinically diagnosed knee OA using

ACR criteria (Altman, 1995), and had knee pain on most days of >40mm on a

100mm visual analog scale (VAS) in their worst knee. Participants were

excluded if they had knee X-rays with joint space narrowing (JSN) of Grade 3

using the Osteoarthritis Research Society International (OARSI)

atlas (Altman, 1986), read by chief investigators (GJ and LM) on diagnostic

radiographs; had other forms of arthritis (including hip osteoarthritis); had

significant knee injury in the last six months; or were unable to provide

informed consent. Participants who were otherwise eligible and those who

had Grade 3 JSN in their worst knee were able to enter the study if JSN was

<3 in the other knee.

A3.2.3 Participants

Participants were screened over the telephone. If they met the inclusion

criteria and did not meet the exclusion criteria, they were invited to attend a


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study centre for screening. Screening and examination was undertaken by a

rheumatologist (GJ, LM) and a nurse (MC, MG, TF). Participants supplied a

blood specimen for serum chemistry, renal function and inflammatory

markers; a urine sample for cartilage metabolites; and had a semi-flexed

knee X-ray. Use of other medication (including pain medicines) was allowed

but kept constant through the trial period where possible. All participants

provided written consent. The study was approved by the Human Research

Ethics Committee (Tasmania) Network and the Northern Sydney Local

Health District Human Research Ethics Committee.

A3.2.4 Interventions

Participants received either 4Jointz cream (active) or identical inert placebo

cream. The active treatment was a combination of a standardized comfrey

extract (200 mg/g) and pharmaceutical grade tannic acid (100 mg/g) plus

other ingredients including aloe vera (300 mg/g), eucalyptus oil (40 mg/g),

and frankincense oil (1.0 mg/g).

Participants were instructed to apply enough cream to coat the knee with a

thin coating which was then massaged in using gentle circular motions for 3–

5 minutes, three times daily. Therefore the daily dose was approximately 3.5

g/day. Participants were supplied with one 100g tube of cream at each visit.

Study medication was stored in a locked cupboard prior to dispensing, and

dispensed when patients successfully completed the screening visit(s).

Treatment continued for twelve weeks, where medication use was

discontinued while maintaining the blind. Participants were re-assessed at

16 weeks.


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A3.2.5 Outcomes

Primary hypotheses were that 4Jointz was superior to placebo at twelve

weeks for change in: knee pain (using the pain intensity VAS and the pain

scale from the Knee Injury and Osteoarthritis Outcome Score Questionnaire

(KOOS)); markers of inflammation (IL-6), and cartilage breakdown (CTX-2).

Secondary hypotheses were that 4Jointz was superior to placebo for change

in: pain between baseline and four and eight weeks of treatment; response

using the OARSI response criteria (Pham, 2004), lower limb muscle strength

and use of paracetamol between baseline and four, eight and twelve weeks.

A3.2.6 Outcome measures

A3.2.6.1 Pain and function

Knee pain intensity was measured using a 100mm visual analogue scale on

four occasions (baseline, four, eight, twelve and sixteen weeks). Participants

were asked “on this line, where would you rate your pain today?”.

Knee pain and symptoms were also assessed using the KOOS questionnaire

on all five occasions (Roos, 1998). These two subscales have nine (pain)

and seven (symptoms) questions, each with five response levels scored from

0–4. Subscales were transformed according to instructions in the original

manuscript (Roos, 1998). The transformed scale had possible values from 0–

100 with zero representing extreme knee pain or symptoms and 100

representing no knee pain or symptoms. Baseline questionnaires were

completed in the clinic. Subsequent questionnaires were completed by mail.

A3.2.6.2 Inflammation and cartilage breakdown

Urine and blood samples were stored at -80°C. Baseline and twelve week

urine samples were assayed for the cartilage breakdown marker CTX-II in

one batch in duplicate using a Human CTX-2 ELISA kit (Cusabio Biotech Co,

Hubei Province, China), and following the manufacturers’ instructions. Urine


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was diluted by half, and absorbance was read at 450nm with reference

wavelength at 570nm. Samples with <1 ng/mL were deemed out of range

and analysed with a value of zero.

Baseline and twelve week blood samples were assayed for the inflammatory

marker IL-6 in one batch in duplicate using a Human IL-6 ELISA MAX Deluxe

SET kit (Biolegend, California, USA), and following the manufacturers’

instructions. Sera was used neat, and absorbance was read at 450nm with

reference wavelength at 570nm. Samples with <1 pg/mL were deemed out

of range and analysed with a value of zero.

A standard curve was run on each plate, in duplicate (R2 >0.997).

Absorbance was read using SoftMax Pro software, which calculated the

standard curves and concentrations for each unknown on a plate by plate

basis.

A3.2.6.3 OMERACT-OARSI response criteria

Response to 4Jointz was assessed using a modified version of the

OMERACT-OARSI set of response criteria (Pham, 2004). Participants were

classed as responding if they had high improvement in pain (using the VAS)

or function (using KOOS function scale) of ≥50% and absolute change ≥20;

or if they had improvement in both pain and function of ≥20% or ≥10. Criteria

for change in participants’ global assessment were not included.

A3.2.6.4 Paracetamol usage

Paracetamol usage was recorded at baseline (along with other medication)

and at each subsequent visit. For participants who did not use paracetamol

daily, the dose taken was averaged to a daily dose over a 28 day month.


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A3.2.6.5 Muscle strength

Leg strength was measured to the nearest kilogram in both legs

simultaneously, using a dynamometer (TTM Muscular Meter, Tokyo, Japan)

as previously described (Scott, 2009). This tests isometric strength,

predominantly of the quadriceps and hip extensors.

A3.2.6.6 Safety

Adverse events were defined as any untoward event occurring during the trial

regardless of whether it was considered medication-related. Serious adverse

events were defined as unplanned hospital admissions, new cancer

diagnoses or death during the 16 weeks of the study. Blood tests were

performed at baseline and 12 weeks to assess safety, and included general

biochemistry, red and white cell parameters and platelet counts.

A3.2.7 Sample size

Sample size for pain intensity using VAS was based on demonstrating a

10mm greater reduction compared to placebo with a SD of 20mm (Langford,

2006; Raynauld, 2004). A change of 10mm reduction on the VAS (compared

to placebo) required 62 participants per group with =0.05 and =0.20.

Therefore, we aimed to enrol 70 participants in each group to allow for

dropouts.

A3.2.8 Randomisation and sequence generation

Participants were randomly allocated to one of two treatment arms (4Jointz

or placebo) using computer generated block randomisation in blocks of four.

The random allocation sequence was automatically generated, and a security

protected central automated allocation procedure was used to allocate

participants to treatment arm 1 or 2. This was then used by one author (LL,

who had no contact with participants) to dispense the allocated medication

for the Hobart participants. Research nurses enrolled participants in the trial,


Page 250

and then gave tubes of cream to each individual patient. The procedure for

Sydney patients was the same except that the pharmacy at the Royal North

Shore Hospital dispensed allocated medication to Sydney participants. The

active treatment and placebo product were visually and aromatically identical.

Participants and staff involved in patient care remained blinded to treatment

allocation throughout the trial.

A3.2.9 Statistical methods

We used Stata 12.0 (StataCorp LP) for statistical analyses. Statistical

significance was set as a p value ≤0.05 (two-tailed). We used a modified

intent to treat (ITT) approach for data analysis, where all patients who were

randomised to receive treatment were included in the analysis. Change in

outcomes were assessed using the difference between the factor at baseline

and follow up and assessed using linear regression. Normality checks were

done using Stata’s pnorm and qnorm functions. Change in CTX-2 and

change in IL-6 both had one highly influential outlier (>99th percentile) which

was omitted from analysis in order to satisfy requirements of normality for

linear regression. Poisson regression was used to compare numbers of

adverse events, with data checked for overdispersion. Change in binary

outcomes were assessed using logistic regression for panel data (xmelogit)

and clustering on ID to account for correlated outcomes within an individual.

Post-hoc analyses on the change in outcomes by sex, OARSI grade and BMI

were also performed, using linear regression. Sensitivity analyses were

performed on estimates of the effect of treatment between baseline and

twelve week, adjusting for covariates where there was a statistically or

clinically significant difference at baseline (OARSI grade, use of paracetamol,

use of glucosamine).


Page 251

Results

A3.3.1 Study participants

Figure A3. shows that a total of 167 participants attended screening for the

study. 34 participants were excluded after initial screening. Most of these

(n=30) had knee OA which was too severe (Grade 3 JSN). The remaining

133 participants were randomised to receive either 4Jointz or placebo. After

twelve weeks of follow-up (the time at which the main outcomes were

assessed), 81% of the cohort had been retained, 88% in the placebo group

and fewer patients (75%) in the intervention group (p=0.03).


Page 252

Figure A3.1: Study flow chart

Table A3.1 shows that participants were predominantly middle aged,

overweight women. One in eight had experienced previous surgery, and the

average pain intensity indicated that these participants were in moderate to

Assessed for eligibility (n=167)

Excluded (n=34)

Met exclusion criteria (n=32):

VAS<40mm (n=1)

JSN Grade 3 (n=30)

Other form of arthritis (n=1)

Declined to participate (n=1)

Other Reasons (n=1):

Referred pain from hip (n=1)

Lost to follow-up (n=3)

Refused to continue (n=3)

Lost to follow-up (n=4) Refused to continue (n=4)

Allocated to PLACEBO (n=64)

Received allocated intervention (n=64)



Non-elective admission for cardiac surgery (n=1)

Allocated to 4JOINTZ (n=69)

Received allocated intervention (n=69)



Rash (n=1)

Increased knee pain (n=1)

Other (n=2)

Allocation

Follow-Up: 8 weeks

Follow-Up: 4 weeks

Randomized (n=133)

Enrollment


Increased pain (n=1)



Rash (n=2)

Other (n=1)

Follow-Up: 12 weeks

Treatment ceases





Rash (n=1)

Unable to contact (n=1)

Follow-Up: 16 weeks


Page 253

severe pain on most days despite being on up to three different pain

medications.

The participants receiving 4Jointz and placebo were well matched. The

groups were different in their use of glucosamine (p=0.04) and number of

pain medicines used (p=0.049), which was predominantly differences in use

of paracetamol and glucosamine.

Table A3.1: Baseline characteristics of study patients

4Jointz Placebo

n=64 n=69

mean (sd) mean (sd)

Age 64.3 (9.8) 65.5 (8.3)

Sex (% male) 45 36

Weight 83.3 (15.9) 81.6 (16.6)

BMI 29.7 (4.9) 29.9 (5.1)

Medication use

Paracetamol (%) 30 41

Average paracetamol dose (mg) 1710 (1374.9) 1475 (1165.7)

Fish oil (%) 30 34

Glucosamine (%) 22 38

COX-2 inhibitors (%) 14 16

Radiographic OA (n,%)*

Grade 0 12 (17) 18 (28)

Grade 1 24 (35) 13 (20)

Grade 2 22 (32) 21 (33)

Grade 3 0 0

Number of pain medicines (n, %)

0 31 (45) 16 (25)

1 18 (26) 17 (27)

2 7 (10) 16 (25)

3 13 (19) 15 (23)

Previous knee surgery, self-reported (%) 10 14

Pain intensity (VAS score) 52.7 (15.7) 53.8 (14.5)

Pain intensity (KOOS) 57.0 (12.7) 56.2 (15.5)

Symptoms score (KOOS) 59.6 (14.9) 58.6 (16)

IL-6 (pg/mL) 5.7 (7.2) 6.4 (13.9)

CTX-2 (ng/mL) 20.8 (48.4) 21.5 (38.5)

*Radiographic OA assessed using OARSI criteria


Page 254

A3.3.2 Outcomes

Data on the main outcomes are shown in Table A3.2. Data was analysed

using all available data points.

Primary hypotheses

For the primary hypotheses of changes between baseline and twelve weeks,

the data shows that the treated group had an significantly greater reduction in

knee pain on the VAS scale averaging 9.9mm (p=0.034) compared to

placebo. It also showed a significant improvement, 5.7 points on the KOOS

pain scale (p=0.047). Neither change in IL-6 (-1.6, 95% CI -4.0 to 0.8; p=0.2)

nor change in cartilage breakdown (2.8, 95% CI -10.6 to 16.1; p=0.68) were

significantly different between baseline and twelve weeks.

Secondary outcomes

The change in pain recorded using the KOOS pain scale was significantly

different by eight weeks, with patients receiving 4Jointz experiencing less

pain (6.1, p=0.025).

Participants receiving 4Jointz also had greater leg strength (2.9 kg, p=0.02)

after twelve weeks of treatment, this result remained statistically significant

after adjustment for baseline differences.

Table A3.2: Effect of treatment with 4Jointz: study outcomes after four, eight and twelve weeks of treatment, using change models

4 weeks 8 weeks 12 weeks 16 weeks

Beta (95% CI) p Beta (95% CI) p Beta (95% CI) p Beta (95% CI) p

n=124 n=112 n=106 n=101

Pain (VAS) -3.0 (-10.4 to 4.4) 0.42 -5.7 (-13.8 to 2.3) 0.16 -9.9 (-19.1 to -0.8) 0.034 -2.4 (-11.6 to 6.7) 0.60

Pain (KOOS) 1.3 (-3.3 to 5.9) 0.58 6.1 (0.8 to 11.4) 0.025 5.7 (0.1 to 11.3) 0.047 0.03 (-7 to 7.1) 0.99

Symptoms 1.7 (-2.6 to 6.0) 0.45 -0.2 (-5.3 to 4.9) 0.94 4.7 (-1.3 to 10.7) 0.12 -2.5 (-8.6 to 3.6) 0.43

Leg strength (kg) -0.02 (-2.4 to 2.4) 0.99 1.9 (-0.6 to 4.5) 0.13 2.9 (0.5 to 5.3) 0.02 1.5 (-1.3 to 4.3) 0.30

IL6 - - -1.6 (-4.0 to 0.8) 0.20 -

CTX-2 - - 2.8 (-10.6 to 16.1) 0.68 - OMERACT-OARSI response criteria¥ 1.2 (0.7 to 2.1) 0.56 1.4 (0.82 to 2.4) 0.22 1.3 (0.8 to 2.2) 0.34 1.1 (0.7 to 2) 0.63

Paracetamol use (yes / no) ‡ 1.0 (0.6 to 1.7) 0.85 1.0 (0.8 to 1.4) 0.82 1.0 (0.8 to 1.2) 0.8 1.0 (0.8 to 1.1) 0.67 Paracetamol dose (in those using at baseline)

-70.7 (-759.9 to 618.6) 0.84

-247.6 (-925.6 to 430.5) 0.46

-404.2 (-1268.8 to 460.4) 0.35

-734.9 (-1615.7 to 145.8) 0.098

The statistics presented are the change in the outcome between baseline and the time point of interest except the response criteria. The number presented is the beta coefficient (and 95% CI) for the additional effect of treatment over that of placebo except where ‡odds ratios or ¥Poisson regression is used, where indicated. Treatment ceased after twelve weeks.

Pa

ge 2

55

Table A3.3: Offset effect- change in study outcomes when treatment ceases (between 12 and 16 weeks of observation)

Beta (95% CI)

n=99 p

Pain (VAS) 9.2 (0.4 to 17.9) 0.04

Pain (KOOS) -6.8 (-13 to -0.5) 0.034

Symptoms -8.5 (-14.1 to -2.8) 0.004

Leg strength (kg) -2.5 (-4.9 to -0.1) 0.04

OMERACT-OARSI response criteria¥ 1.1 (0.7 to 2.0) 0.63

Paracetamol use (yes / no) ‡ 0.2 (0.02 to 1.5) 0.11

Paracetamol dose (in those using at baseline) -308.9 (-802.8 to 185) 0.21

Statistics presented are the change in the outcome between baseline and the time point of interest except the response criteria. The number presented is the beta coefficient (and 95% CI) for the additional effect of treatment over that of placebo except where ‡odds ratios or ¥ Poisson regression is used, where indicated. Paracetamol offset effect (change between 12-16 weeks) is adjusted for baseline paracetamol use

Pa

ge 2

56


Page 257

A3.3.3 Individual outcomes

A3.3.3.1 Pain intensity (using visual analog scores)

Figure A3.2 shows that pain intensity decreased in both groups at the

beginning of the trial period and plateaus in the placebo group after eight

weeks of treatment. By twelve weeks of treatment, difference in the change

scores between groups were statistically significant (-9.9 mm, 95% CI -19.1

to -0.8; p= 0.034), see Table A3.. This remained significant after adjustment

for differences in the group at baseline (baseline paracetamol and

glucosamine use, and OARSI grade). After the treatment was discontinued,

the differences between the groups rapidly reduced (9.2mm (95% CI 0.4 to

17.9); p=0.04 (Table A3.3).

Figure A3.2: Pain intensity (using the visual analog scores) over sixteen weeks of treatment, by treatment received


Page 258

A3.3.3.2 KOOS results

Figure A3.3 shows that pain intensity (as measured using the KOOS

questionnaire) reduced in both groups at the beginning of the trial period

(note: “no pain” is zero on the KOOS scale, not 100) and plateaus in the

placebo group after four weeks of treatment. By eight weeks of treatment,

the difference in the change scores between groups were statistically

significant (6.1, 95% CI 0.8 to 11.4; p= 0.025), this difference remained

significant at twelve weeks (5.7, 95% CI 0.1 to 11.3; p= 0.047), see Table

A3.. After adjustment for baseline paracetamol and glucosamine use, and

OARSI grade, the effect of treatment was no longer significant, but the

magnitude of the effect was similar (5.2, p=0.12) and none of the covariates

were statistically significant. After the treatment was discontinued, the

differences between the groups rapidly decreased (-6.8, 95% CI -13 to -0.5;

p=0.034, Table A3.3).

For symptoms, differences in change scores between the group receiving

placebo and 4Jointz were not statistically significant at any time point, except

between twelve and sixteen weeks when the treatment was discontinued (-

8.5, -14.1 to -2.8; 0.004).


Page 259

Figure A3.3: Pain intensity (as measured using the KOOS questionnaire) over sixteen weeks of treatment, by treatment received

Figure A3.4: Symptom scale, as measured using the KOOS questionnaire, over sixteen weeks of treatment, by treatment received

01

02

03

04

05

06

07

08

0

Sym

pto

m s

ca

le(K

OO

S)

0 4 8 12 16Visit (weeks)

Placebo 4Jointz

95% CI


Page 260

A3.3.3.3 Cartilage breakdown

Changes in the cartilage breakdown marker CTX-2 were not significant

between baseline and twelve weeks (See Table A3.2, Figure A3.5), and

remained non-significant after adjusting for baseline differences.

Figure A3.5: CTX-2, by treatment received


Page 261

A3.3.3.4 Systemic inflammation

Changes in the measure of systemic inflammation (IL-6) were not significant

between baseline and twelve weeks (See Table A3.2, Figure A3.6), and

remained non-significant after adjusting for baseline differences.

Figure A3.6: IL6, by treatment received


Page 262

A3.3.3.5 Paracetamol use

Usage of paracetamol was assessed in two ways, firstly whether participants

were using paracetamol or not (prevalence of paracetamol use), and daily

dose of paracetamol used amongst persons reporting paracetamol use at

baseline.

Treatment with 4Jointz did not change prevalence of paracetamol use (using

compared to not using) over the duration of the trial, nor did it change when

treatment ceased after week 12, after adjustment for baseline paracetamol

use (p=0.11, Table A3.3). More participants in the placebo group used

paracetamol at baseline than persons receiving 4Jointz (see Table A3.2,

Figure A3.7), but this difference also did not reach statistical significance

(p=0.09).

Figure A3.7: Proportion of participants using paracetamol over sixteen weeks of treatment, by treatment received


Page 263

Figure A3.8 shows that among persons using paracetamol at baseline (n=47)

treatment with 4Jointz decreased the daily dose of paracetamol taken over

the duration of the trial (weeks 1-12) by 404mg but this did not reach

statistical significance (p=0.35). Similarly, daily dose of paracetamol was not

different between groups when treatment ceased (week 12-16, see Table

A3.3). Variation within the groups (as seen with the 95% confidence intervals

of the estimates) was large compared to the observed effect sizes.

Figure A3.8: Daily dose of paracetamol (mg) over sixteen weeks, in participants using paracetamol at baseline, by treatment received


Page 264

A3.3.3.6 Leg strength

Figure A3.9 shows that the groups receiving placebo and 4Jointz began to

diverge in their leg strength measures by eight weeks, and by twelve weeks

the differences in change scores between the two groups had reached

statistical significance (2.9, 95% CI 0.5 to 5.3; p=0.02), see Table A3.2. Leg

strength remained significant after adjustment for baseline differences and

reduced when treatment ceased (-2.5kg, p=0.04).

Figure A3.9: Leg strength over sixteen weeks of treatment, by treatment received


Page 265

A3.3.3.7 OMERACT – OARSI response criteria

Figure A3.10 shows the response to treatment using a modified form of the

OMERACT-OARSI response criteria. Response to treatment was not

different between participants receiving 4Jointz and placebo, at any time

point.

Figure A3.10: Response to treatment using a modified version of the OMERACT – OARSI response criteria, by treatment received


Page 266

A3.3.4 Post-hoc analyses

Additional analyses were conducted on the pain measures. These were

analyses decided after the trial concluded, and are therefore of a hypothesis-

generating rather than a hypothesis-answering nature.

A3.3.4.1 Gender

We investigated the effect of treatment with 4Jointz (vs placebo) on pain

intensity on men compared to women; persons with different grades of

radiographic knee OA, initial pain score (above / below a VAS of 50), and

BMI (above / below a BMI of 25).

Women responded better to treatment than men, using both the VAS pain

intensity score and the KOOS pain scale (see Table A3.4, Figure A3.11 and

Figure A3.12).

Table A3.4: Change in pain scores between baseline and twelve weeks, by gender and treatment group

Change in n Placebo n 4Jointz Diff p

VAS score

Females 36 -12.9 (-21.7 to -4.1) 24 -29.7 (-37.1 to -22.2) -16.8 0.008

Males 20 -20.4 (-31.8 to -8.9) 26 -21.6 (-31.4 to -11.7) -1.2 0.87 KOOS pain score

Females 35 1.9 (-2.8 to 6.6) 23 10.6 (5.2 to 16.0) 8.7 0.018

Males 19 11.0 (6 to 16) 26 10.9 (3.8 to 18.1) -0.1 0.99


Page 267

Figure A3.11a and b: Effect of treatment on pain intensity in women and men, by treatment received


Page 268

Figure A3.12 a and b: Effect of treatment on KOOS pain score in women and men, by treatment received


Page 269

A3.3.4.2 OARSI grade and BMI

The effect of treatment by radiographic staging of OA was also investigated,

using OARSI grade, and by body mass index (below / above a BMI of 25).

After twelve weeks of treatment, 4Jointz was effective in treating persons

with OARSI grades of 0 and 1 but not those with OARSI grade 2 (see Figure

A3.13).

Treatment appeared more effective in participants who were overweight or

obese, but this did not reach statistical significance. The effect size was

similar in participants with BMI below 25 as above 25 so this may merely

reflect the smaller number of persons in the healthy weight range in the

sample.

Table A3.5: Change in VAS score between baseline and twelve weeks, by OARSI grade and body mass index.

n PLACEBO n 4Jointz Diff p

OARSI grade

0 or 1 29 -9.9 (-20.3 to 0.5) 26 -26.0 (-31.6 to -20.4) -16.1 0.009

2 17 -22.3 (-33.7 to -10.9) 16 -29.6 (-42 to -17.3) -7.3 0.36

BMI<25 9 -20.6 (-39.2 to -1.9) 7 -31.1 (-58.6 to -3.7) -10.6 0.45

BMI 25+ 47 -14.6 (-22.2 to -7.0) 41 -24.4 (-30.9 to -17.9) -9.8 0.06


Page 270

Figure A3.13a and b: Effect of treatment on pain intensity in persons by OARSI grade (0 and 1 vs 2), by treatment received


Page 271

A3.3.5 Adverse events

Adverse events were common in this cohort, with 61% (n=62) of the placebo

group and 72% (n=66) of the 4Jointz group experiencing at least one

adverse event. Differences in prevalence and actual number of events were

not significant (Table A3.6).

One aspect of the adverse events was significantly different between persons

receiving 4Jointz and placebo. Localised skin irritation at the site of

application (“rash”) was significantly higher in patients receiving 4Jointz (risk

ratio 13.2, p=0.013). Participants experiencing localised irritations were

advised to cease using the treatment, then rechallenge with cream after a

few weeks. Treatment ceased if the rash recurred. Rashes were severe

enough to discontinue the study drug in four participants (26% of those with

rash) (Table A3.6). One participant had a serious adverse event, which was

a non-elective hospital admission where they received a cardiac stent. We

think this is unlikely to be causally related to the use of 4Jointz. Over 40% of

participants had at least one change in their blood results between baseline

and twelve weeks, but differences between participants receiving 4Jointz and

placebo were not significant.

Overall, these results show that 4Jointz is safe and effective amongst 50-80

year old adults with clinical diagnosed knee osteoarthritis. The only adverse

event experienced more commonly in persons receiving 4Jointz compared

those receiving placebo for knee pain is a localised skin irritation, which

recurred in a minority after a break in treatment.


Page 272

Table A3.6: Prevalence and number of adverse events, by treatment received

Placebo 4Jointz p

n=62 n=67

Adverse events Prevalence of at least one adverse event (n, %) 38 (61) 48 (72) 0.47

Number of adverse events 67 78 0.85

Prevalence of (n, %)

Rash 1 (1.6) 14 (21.2) 0.013

Upper respiratory tract infection 11 (17.7) 10 (15.2) 0.69

GI Upset 4 (6.5) 2 (3) 0.37

Headache 3 (4.8) 6 (9.1) 0.38

Increased knee pain 3 (4.8) 2 (3) 0.60

Knee swelling 1 (1.6) 1 (1.5) 0.96

Abnormal blood results 24 (41) 29 (44) 0.82

Elective hospital admissions 3 (4.8) 1 (1.5) 0.31

Serious adverse events Number of non-elective hospital admissions 0 1

Cancer 0 0

Death 0 0


Page 273

Discussion

This study has demonstrated that 4Jointz is a safe and effective topical

treatment for moderate to severe knee OA in participants aged 50-80 years.

4Jointz was effective in reducing pain at twelve weeks using both the VAS

and the KOOS scales, and by 8 weeks using the KOOS scale. 4Jointz also

increased quadriceps strength by an average of 3 kg after 12 weeks. It had

no effect on systemic inflammation or cartilage breakdown over twelve weeks

of treatment.

This clinical trial has the longest reported duration of use of comfrey for

osteoarthritic knee pain, with previous trials being of three (Grube, 2007) or

six weeks duration (Smith and Jacobson, 2011). Patients had the largest

responses to treatment at the last occasion during treatment in this study (12

weeks) and therefore if treatment continues past this time, patients may

continue to benefit.

Treatment was discontinued after twelve weeks and pain, other symptoms

and leg strength significantly worsened. This suggests that there is a rapid

offset, and continuing treatment longer than twelve weeks may result in

continuing benefit.

The results from this study are consistent with those of two other

trials (Grube, 2007; Smith and Jacobson, 2011), in that all support a role for

comfrey as a topical treatment for knee pain and OA. However, it is not

possible to directly compare results between all studies because the patient

populations are different, and the studies use different outcome measures,

requiring in-depth analysis of the results to make any reasonable

comparisons.


Page 274

Grube et al (2007) included patients with long term knee pain (not clinically

diagnosed OA) and with pain scores (on VAS) as low as 23mm and patients

discontinued taking other medications suggesting that participants may not

have knee OA, or are earlier in the disease course. The larger effect

observed in this study is consistent with our results in early OA. Omitting

participants taking analgesics or anti-inflammatory medications would have

ruled out nearly 60% participants in the 4Jointz study and thus these results

should be seen as an additional benefit of 4Jointz rather than the only

benefit. Grube et al (2007) also observed a much greater reduction in pain

with the use of comfrey than this study at a comparable time point. This may

be due to the use of an aggregate of the WOMAC subscales “pain at rest”

and “pain on movement”. This is misleading as adding these values is not a

representation of either pain scale, does not represent the actual pain levels

of the patients and artefactually doubles the apparent magnitude of benefit.

Since post hoc analyses suggested that treatment may be most effective in

women and those with milder radiographic osteoarthritis, future research

should consider studies specifically in these populations.

We observed clinically important changes in self–rated outcomes in the

group receiving placebo as well as those receiving 4Jointz. These were most

evident with pain but we also observed them in the KOOS symptom score.

This is consistent with a meta-analysis of the placebo effect in clinical trials of

treatment for OA (Zhang, 2008), in which effect sizes of 0.26 were reported

for placebo in trials of herbal treatments. This highlights the importance of

using randomised controlled trials to assess the efficacy of all pharmaceutical

treatments.


Page 275

The side effect profile observed was similar to that reported in a pilot study of

4Jointz (Smith and Jacobson; Grube, 2007). Overall 4Jointz appears safe

and well tolerated. Most importantly, the renal toxicity associated with

pyrrolizidine-type alkaloids, associated with oral use of comfrey (Stickel and

Seitz, 2000) appears absent in topical use, as expected. The skin irritation

appears causally related to the use of 4Jointz as it reversed on cessation of

treatment, and only reappeared in around one fifth of those with rash.

We supplied participants with one tube of cream per month. We have

observed clinically significant changes with one tube of cream per month or

about 3.5g/day. Since only one dose of 4Jointz was used in this study we

cannot compare with other concentrations. However, Smith et al compared

formulations of, 10% and 20% comfrey extract and pseudoplacebo, and

whilst both were superior to placebo, the treatment arms were not

significantly different from each other (Smith and Jacobson, 2011).

Strengths of this study include the comparatively long duration of treatment,

the defined study population and standardised meaningful outcome

measures. The major limitation of this study is the difference in dropout rates

between the groups receiving placebo and 4Jointz, with more patients

ceasing treatment in the 4Jointz group. This included but was not limited to

patients who experienced rash and were advised to cease treatment.

Conclusions

Topical treatment using 4Jointz is a safe and effective treatment for the

symptoms of OA. In particular, it reduces pain and increases muscle

strength, but has no effect on systemic inflammation or cartilage breakdown

over twelve weeks of treatment.


Page 276

Appendix 4: Published manuscripts

Page 277

Appendix 4: Published manuscripts

This Appendix has been removed for

copyright or proprietary reasons

Appendix 4

Contains published article in:

http://www.biomedcentral.com/1471-2474/13/168

Laura Laslett, Stephen J Quinn, Tania M Wizenberg, Kristy Sanderson, Flavia Cicuttini, and Graeme Jones. 2012, A prospective study of the impact of musculoskeletal pain and radiographic osteoarthritis on health related quality of life in community dwelling older people. BMC Musculoskeletal Disorders: 13, 168. doi:10.1186/1471-2474-13-168.

http://www.biomedcentral.com/1471-2474/13/168

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